Article Text
Abstract
After initial diagnosis and treatment, patients presenting to hospital with acute heart failure (HF) are assessed and managed by the hospital HF team. Further investigations are carried out to confirm the diagnosis; existing guideline-directed medical therapies are optimised; and new treatments are initiated to stabilise the condition, manage symptoms, and reduce morbidity and mortality. A wide range of diagnostic tests and therapeutics are established for HF with reduced ejection fraction, while options for HF with preserved ejection fraction have been limited. However, repurposing of drugs originally developed for other conditions (eg, sodium-glucose co-transporter 2 inhibitors and glucagon-like receptor 1 antagonists) for use in people with heart failure and extended use of medications traditionally restricted to reduced ejection fraction, such as mineralocorticoid receptor antagonists (eg, spironolactone) and angiotensin-neprilysin inhibitors (eg, sacubitril–valsartan) in those with an EF>40% is challenging established practice and increasing the options for optimisation of long-term management of patients with HF, across the entire ejection fraction spectrum. Integral to the management of chronic HF is the need to consider approaches to identify deterioration between scheduled visits, including annual electrocardiography and N-terminal pro B-type natriuretic peptide monitoring in primary care. Remote monitoring, including alert-based monitoring for patients with implanted devices, may help to identify worsening HF or deterioration between scheduled clinic visits. Questions remain around optimal diuretic treatment (eg, infusion vs bolus dosing during periods of decompensation and converting to oral furosemide or bumetanide); use of beta blockers in HF patients with atrial fibrillation (AF) and midly reduced or normal ejection fraction; whether mineralocorticoid receptor antagonists should be used in HF patients with higher ejection fraction beyond the control of blood pressure, and the choice between spironolactone and eplerenone; how sacubitril–valsartan should be used in patients with ejection fraction>40%; in which setting drugs should be optimised following discharge, and whether cessation of medications is appropriate after recovery in ejection fraction.
Data availability statement
No data are available.
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Background
Following initial diagnosis and immediate management of patients presenting with signs and symptoms of acute HF to the emergency room (ER) or referred by their primary care clinicians, patients are ideally assessed and managed by dedicated HF teams. Further investigations are performed to confirm the patient’s diagnosis, existing guideline-directed medical therapies (GDMT) are optimised, and new treatments initiated to stabilise their condition, manage signs and symptoms, and reduce morbidity and mortality.1 2 A suite of investigations and treatments are well established for heart failure with reduced ejection fraction (HFrEF), while options for those with heart failure with mildly reduced and preserved ejection fraction (HFmREF and HFpEF) are limited.
The availability of new tests, novel drugs, and repurposing of drugs originally developed for the treatment of other conditions is challenging established practice and increasing the options for optimisation of long-term management of patients with HF. In this article, we consider expanded use of existing investigations for pre-discharge and long-term monitoring of HF, the place of new drugs and those developed for different conditions in the HF treatment pathway, and highlight currently unanswered questions and barriers to optimal management.
Targets for treatment in acute heart failure
Diuresis
Decongestion, the initial aim for treatment of acute HF, is achieved using diuretics. In cases of moderate to severe congestion, intravenous furosemide is the accepted first-line treatment to alleviate symptoms and signs of HF,3 although uncertainties remain around the use of infusion vs bolus dosing and on converting to oral furosemide or bumetanide.
Loop diuretics combined with thiazide diuretics are commonly used in the treatment of acutely decompensated HF. However, other diuretics have also been shown to potentiate the effects of loop diuretics. Acetazolamide is a carbonic anhydrase inhibitor which reduces proximal tubular absorption of sodium and thereby potentially increases the efficacy of loop diuretics. In the UK acetazolamide licensed for the treatment of glaucoma and seldom considered for the treatment of HF. In the Acetazolamide in Decompensated Heart Failure with Volume Overload (ADVOR) multicentre randomised control trial, intravenous acetazolamide was compared with placebo, in addition to intravenous loop diuretics, in patients with acutely decompensated HF. Treatment with acetazolamide, a carbonic anhydrase inhibitor that acts on the proximal collecting tubule, was shown to be safe and effective; associated with higher rates of successful decongestion at day 3 (42.2% vs 30.5%; p<0.001) and shorter length of hospital stay (8.8 vs 9.9 days; p=0.016) compared with placebo.4 It is unclear whether the results simply reflect the effects of a higher cumulative diuretic dose, or are unique to the acetazolamide-loop diuretic combination.
In acute HF, the dosing of diuretics is an imprecise practice, largely dependent on clinician judgement. Although urinary spot sodium testing is not widely used in routine clinical practice, it is described in clinical practice guidelines.2 Furthermore, data from small-scale post-hoc and retrospective analyses suggest that urinary sodium may be a useful clinical biomarker to predict response to and guide dosing of diuretics in patients with acute HF (figure 1). Low urinary sodium is associated with reduced diuresis, longer length of stay, and reduced weight loss. The Renal Optimisation Strategies Evaluation Acute Heart Failure (ROSE AHF) study reported that patients with higher urinary sodium levels had reduced rates of death and HF rehospitalisation than those with lower urinary sodium levels (figure 1).5 6
Place of care for people with acutely decompensated chronic heart failure is also an important consideration that should not be overlooked. While hospitalisation is typically necessary for the management of decompensated HF and for administration of intravenous diuretics, it is important to recognise that hospital admission should not be considered benign, particularly for frail and elderly patients who are at higher risk of nosocomial infection and hospital-associated deconditioning.7 There is growing data to indicate that selected patients experiencing congestion could potentially be managed in an outpatient setting.8 In the USA, 1% of all HF care visits involve outpatient intravenous diuretics.9 In contrast, the utilisation of ambulatory intravenous and subcutaneous diuretics in the UK, within outpatient or domiciliary settings, has until recently been limited to a small number of centres.7 However, the adoption of domiciliary and ambulatory intravenous diuretics, overseen by heart failure teams, is becoming increasingly popular through virtual wards for heart failure. Currently, the SUBCUTaneous Preparation of Furosemide to Facilitate Early Supported Discharge in Heart Failure (SUBCUT-HF II) trial, is underway to explore outpatient strategies for diuresis. This study is investigating the use of subcutaneous furosemide to facilitate the early discharge of decompensated patients.10
Beta blockers
There is unequivocal evidence indicating strong prognostic benefit of beta blockers in patients in sinus rhythm and below-normal left ventricular ejection fraction (LVEF),11 but use of these drugs in patients with concomitant atrial fibrillation for reasons other than rate control, in and those with higher ejection fractions is often debated, as the evidence is limited and less clear. Beta blockers are reported to have neutral effects on hard outcomes in patients with atrial fibrillation and heart failure with mildly reduced ejection fraction (HFmrEF) or HFpEF, with limited prognostic benefit beyond rate control in these patients—i.e. no decrease in mortality or cardiovascular hospitalisation observed (figure 2).11 In this capacity, the European Society of Cardiology (ESC) guidelines recommend initiation and titration of a cardioselective beta blocker for short- and long-term rate control in this patient group.3
Digoxin
Use of digoxin for rate control in patients with HF and atrial fibrillation has been the subject of discussion in recent years. A meta-analysis of digoxin in atrial fibrillation studies indicated increased mortality associated with use of digoxin, irrespective of the presence of heart failure (figure 3).12 However, it has been postulated that these safety findings may reflect the fact that digoxin tends to be used in older, frailer patients in whom chronic kidney disease is also more prevalent. Uncertainty therefore remains over a number of issues, including which patients should start digoxin, whether digoxin should be stopped in patients whose heart rate is optimally controlled with a beta blocker, whether digoxin levels should be routinely monitored (as per the Digitalis Investigation (DIG) Group trial),11 13 and whether additional monitoring is needed in patients with heart failure and chronic kidney disease.
Other treatments
Mineralocorticoid receptor antagonists (MRAs) have been shown to reduce morbidity and mortality in patients with HFrEF and are strongly recommended in patients with significantly reduced ejection fraction (LVEF<40%). While MRAs have been shown to improve indices of cardiac structure and function in patients with HFpEF, there is currently no primary evidence indicating a prognostic benefit in this patient group.14 15 In the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist (TOPCAT) study, where patients with HFpEF (LVEF≥45%) were treated with spironolactone, no reduction in the primary composite endpoint of cardiovascular death, cardiac arrest, or heart failure hospitalisation was observed compared with placebo.16 However a subsequent post-hoc analysis of TOPCAT reported a differential effect of spironolactone according to ejection fraction and sex, with reductions in the primary composite endpoint observed in patients with LVEF<55%, primarily driven by a reduction in heart failure hospitalisations in men with LVEF 45–55%. By comparison, no real benefit of treatment was observed in patients with LVEF>65% (figure 4).17 Given the differential effect of MRAs according to ejection fraction and data to indicate a reduction in heart failure hospitalisations, their use in the setting of heart failure with LVEF<55% may be considered beneficial. Consequently, the clinical use of MRAs in heart failure patients with LVEF>40% carries a class 2b recommendation in patients with HFmREF in the 2023 focused update of the 2021 ESC heart failure clinical practice guidelines, while American guidelines extend this to also include patients with an LVEF>50%).2 18 19 Whether these drugs should be used in patients with higher ejection fractions beyond control of blood pressure is an area of active research, as is the choice between spironolactone, eplerenone and non-steroidal MRAs.
Angiotensin-converting enzyme (ACE) inhibitors are recommended for the first-line treatment of HFrEF due to compelling evidence from landmark clinical trials demonstrating a convincing mortality benefit and reduction in HF hospitalisations associated with their use.1 2 20 European HF guidelines continue to recommend ACE inhibitors as first-line treatment for patients with HFrEF, with ARNis positioned as a replacement for ACE inhibitors. De-novo ARNi treatment in ACE inhibitor-naive patients is supported by a class IIb recommendation.21 By comparison, in the American HF guidelines based on recent expert consensus guidance, ACE inhibitors have now been superseded by ARNis for the first-line treatment of chronic HF. Angiotensin-converting enzyme inhibitors are indicated for those unable to tolerate an ARNi, and ARBs are for indicated when ARNi or ACE inhibitor use is not feasible.18
To avoid the pitfalls of slow sequencing, data indicating rapid improvements in health status, and to simplify optimisation of medications, there is growing interest in de-novo use of ARNis in patients with newly diagnosed HFrEF, including initiation in hospitalised patients with acute HF prior to discharge. PIONEER-HF, reported greater reductions in N-terminal pro- brain natriuretic peptide (NT-proBNP) in the sacubitril-valsartan arm compared with controls, with safety outcomes comparable between the two groups.22 23
ARNis are less commonly used in the UK in individuals with EF>40%. The Prospective Comparison of ARNI with ARB Global Outcomes in HF with Preserved Ejection Fraction (PARAGON-HF) study investigated the impact of ARNIs in patients with HFpEF.24 While the study did not meet its primary endpoint, multivariate analysis revealed a differential treatment effect based on ejection fraction, indicating a therapeutic benefit in those with lower left ventricular ejection fraction (LVEF). Notably, patients with an LVEF less than the median (LVEF≤57%) experienced a 22% reduction in the primary composite endpoint of cardiovascular death and HF hospitalisations. The treatment effect of sacubitril–valsartan was observed to vary according to sex, with a 27% greater reduction in the primary composite outcome observed in women compared to men.25 Several factors may contribute to this observation, and one potential explanation lies in the higher 'normal' ejection fractions typically found in women. Systolic impairment in women may occur at higher ejection fractions compared with men, reflected in the different ejection fraction cut offs used to define normal ejection fraction based on sex.2
Regarding patients with EF>40% and recent exacerbation of HF, data from two recent publications shed light on the benefits of sacubitril-valsartan compared with valsartan in individuals with HF and EF>40% experiencing worsening HF; a more acute setting than has been previously studied. PARAGLIDE-HF, was a randomised controlled-trial that examined sacubitril-valsartan in worsening HF and higher EFs. Initiated without a run-in period, the trial included patients with an EF>40%, within 30 days of a worsening HF event. Results reported a significant 15% greater reduction in time averaged NT-proBNP with sacubitril-valsartan, compared with the valsartan group.26 In a subsequent pooled analysis encompassing patients from PARAGLIDEHF and 622 PARAGLIDE-like patients enrolled in PARAGONHF (individuals with a HF hospitalisation within 30 days), the study reported a 22% reduction in the primary endpoint of total worsening HF events and cardiovascular deaths within the sacubitril valsartan group, with the greatest effect observed those with an EF<60%. As this was a post hoc pooled analysis, the data is hypothesis generating rather than hypothesis proving. Nevertheless it signals evidence of benefit of sacubitril-valsartan in acute HF settings in people with higher ejection fractions.27
Together, these findings provide more data to support use of ARNI’s in patients with LVEF>40%. In 2021, the US Food and Drug Administration guidance expanded to include consideration of sacubitril–valsartan in patients with HF and 'below normal' ejection fraction, noting that the effect is most clear in those with reduced ejection fraction.28 The 2022 American guidelines for the management of HF align with this shift, recommending ARNi use in HF patients with 'below normal ejection fraction'.2 18 Despite these recommendations, the current UK licence for sacubitril–valsartan does not cover patients with HFmrEF or HFpEF.29
Drugs affecting the Cardio–renal–metabolic axis
Cardiovascular, renal, and metabolic considerations are important in patients with HF. Type two diabetes and obesity are common comorbidities that may be implicated in the pathogenesis of HF and may contribute to poor functional status. In recent years, two drug classes—the sodium-glucose co-transporter 2 (SGLT2) inhibitors and glucagon-like peptide 1 (GLP-1) agonists—developed to improve glucose control in diabetes have changed the treatment landscape for people with heart failure.
Sodium-glucose Co-transporter 2 inhibitors
Based on the EMPagliflozin outcomE tRial in patients With chrOnic heaRt Failure With Reduced Ejection Fraction (EMPEROR-Reduced) and Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) study, these two SGLT2 inhibitors have licensed indications in patients with stable HFrEF (LVEF≤40%). However, new data also indicates clinical benefit of SGLT2 inhibitors in patients hospitalised with acute HF, and in patients with chronic HFpEF.30 31 The EMPEROR-Preserved trial demonstrated that treatment with empagliflozin reduced the risk of cardiovascular death and heart failure hospitalisation in patients with HFpEF, irrespective of the presence of diabetes. This ground-breaking study, the first of its kind, enrolled patients with stable symptomatic HFpEF and ejection fraction>40%, randomising them to empagliflozin or placebo. Results showed significant reductions in cardiovascular death (7.3% vs 8.2%; HR (HR) 0.91 [95% CI 0.76 to 1.09]) and HF hospitalisation (8.6% vs 11.8%; HR 0.71 [95% CI 0.60 to 0.83]) in the empagliflozin group compared with placebo. Notably, the primary composite endpoint reductions were primarily driven by a decrease in HF hospitalisations.31 Dapagliflozin has also been shown to reduce the combined risk of worsening HF or cardiovascular death in patients with HF and mildly reduced or preserved ejection fraction. Consequently, NICE have approved use of SLGT2 inhibitors in patients with HF across the EF spectrum, irrespective of whether or not the patient is diabetic. Like with ARNI’s, treatment benefits appear attenuated in patients with LVEF≥60%.
For patients with HF or established atherosclerotic disease, the National Institute for Health and Care Excellence (NICE) recommends that SGLT2 inhibitors should be considered as part of the first-line treatment of diabetes, given that it is associated with no risk of hypoglycaemia or weight gain, has efficacy across the range of renal function, and has cardiovascular, metabolic, and renal benefits.32 Whether use of SLGT2 inhibitors in patients with HF without diabetes reduces the risk of future diabetes remains uncertain.
Glucagon-like receptor 1 agonists
For patients with HF and obesity, lifestyle advice includes a recommendation to adopt a balanced diet and take regular exercise to aid weight loss. However, in many instances, diet and exercise alone are not always effective. GLP-1 receptor agonists, originally developed for the treatment of diabetes, have more recently been shown to be effective for weight loss in obese or overweight patients, with and without diabetes. Numerous studies with different GLP-1 receptor agonists have shown reductions in weight in patients with diabetes33–35 and significant and sustained reductions in weight compared with placebo in obese patients with and without diabetes.36 37 The optimal treatment of patients with HF and diabetes should be discussed by the cardiometabolic multidisciplinary team, and patients with HF and obesity could be referred to weight management services with a view to considering the role of these drugs.
The recent STEP-HFpEF and STEP HFpEF DM studies represent a major milestone in medical research, marking the first time a diabetes and weight-loss drug has demonstrated significant efficacy in reducing HF symptoms. This discovery holds significant promise for transforming global treatment approaches for millions of individuals with this condition.
In these studies, once weekly Semaglutide titrated to a dose of 2.4 mg demonstrated effectiveness in improving symptoms and exercise capacity in individuals with obesity-related heart failure. As expected significant reductions in body weight were also observed. Relevant to effects on modifying heart failure, significant reductions in C-reactive protein (CRP) and NT pro BNP were observed in the treatment arms of both studies.38 39
The implications of these findings are relevant, potentially heralding a paradigm shift in the management of HFpEF. The discovery presents new opportunities for the utilisation of this drug and providing hope for individuals with this type of HF, where viable treatment options have traditionally been scarce.
Cessation of medications after a recovery in ejection fraction
Variations in ejection fraction are common across all HF phenotypes but are most common in those with mid-range ejection fractions. Transition from HFmrEF towards preserved LVEF has been reported in 25–44% of patients and towards reduced LVEF in 16–33% of patients.40 Certain clinical characteristics, aetiologies, and treatments increase the likelihood of either recovery or reduction in ejection fraction.41
Therapy withdrawal in REcovered Dilated cardiomyopathy–Heart Failure (TRED-HF) was an open-label, pilot, randomised trial comparing phased withdrawal with continuation of pharmacological treatment for HF in patients with dilated cardiomyopathy and recovered ejection fraction.42 This study found a high rate of relapse when treatment was withdrawn (44%) compared with no relapse in those who continued treatment, and the authors concluded that, without robust predictors of sustained recovery, treatment should be continued indefinitely. The generalisability of the results of this highly selective, small, open-label, pilot study to other scenarios, including treatment with sacubitril–valsartan and SGLT2 inhibitors and in patients with a precipitating factor (eg, toxin-, tachycardia-, peripartum- or viral-related cardiomyopathy) that has been ameliorated, is unclear.
Overall, in the absence of any other evidence and given the potential harm if medications are withdrawn, ACE inhibitors, beta blockers and MRAs should be continued unless there is a clinical reason to discontinue.
Detecting clinical deterioration between scheduled appointments
Patients may deteriorate between scheduled follow-up appointments, so it is important to consider approaches to identify deterioration between scheduled visits. Annual electrocardiography for patients with heart failure, as recommended by NICE,1 can identify patients with progressive broadening of the QRS complex, who may benefit from cardiac resynchronisation therapy. NT-proBNP has an established role for diagnosis and prognostication in HF. However, studies of serial natriuretic peptide testing to guide pharmacotherapy and management in HFrEF have produced conflicting results, and for now this remains an area of primary research. Remote monitoring, including alert-based monitoring for patients with implanted devices, may help to identify unstable or deteriorating patients between scheduled clinic visits- but again outcomes data to show that this approach translates to improved patient outcomes are awaited.
Methods
A group of experts gathered for an in-depth consideration of the management of patients with heart failure following stabilisation of acute signs and symptoms and in the long term. Following a brief presentation, we drew on our clinical and research experience to identify shortcomings in the current approaches and guidelines for long-term management. Case studies, featuring distinct presentations of HF in two patients, were provided to aid the discussion. We further discussed approaches to educate the public and improve clinical practice, including suitable treatments to optimise and maintain heart function.
Discussion
Traditionally, the drugs that comprise GDMT for HF have been introduced gradually in a stepwise fashion, with one drug being introduced and uptitrated before another is initiated, also bearing in mind any cardiovascular drugs the patient may already have been taking before their admission event. With the advent of SGLT2-inhibitors, triple therapy has been replaced by quadruple therapy - this has paved the way for new approaches to drug sequencing. For de novo cases who have been hospitalised, the treatment initiation process may begin prior to discharge, but with hospitals under pressure in terms of bedspace and resourcing, it is difficult to provide adequate time to initiate and uptitrate in a considered manner prior to early discharge. For these patients, the recommended 2 week review following discharge presents an opportunity to further optimise medications – which also enables stabilisation of patients before treatment begins in earnest – but unless expedited the process of optimisation can take many months, delaying the benefits for patients and requiring more intensive clinical input. Considering the mortality benefit associated with these medications, we can ill-afford to procrastinate when it comes to optimisation of disease modifying medications. Supported by clinical practice guidelines and clinical trial data, many within the HF community are adopting a rapid sequencing protocol, where drugs are introduced in parallel rather than slowly and sequentially and, in some cases, titration is supported by primary care.43 To further tackle treatment inertia HFrEF drug treatment scores that are visible to patients and clinicians to prompt initiation and/or titration of sub-optimally dosed foundational therapies are being utilised, but require further validation.44
Specialist heart failure nurses can provide continuity between secondary and primary care prescribing. Community pharmacists are ideally placed to support uptitration, but they are also under-resourced and working across specialties. Furthermore, they will need the support of cardiologists and HF teams if they are to be active in medicines management. A hybrid shared-care approach is perhaps most pragmatic, with secondary care introducing drugs initially, so that community teams are optimising the dosing, but this may require titration of medications like sacubitril-valsartan to be devolved from specialist teams. Despite personalised management plans being in place, it can be easy for patients to slip through the gaps due to lack of communication between secondary and primary care and inconsistent follow-up to check whether recommendations are being followed. Clear guidance in discharge summaries, locally agreed shared-care protocols, individualised plans in selected cases and a designated responsible clinician or named nurse, are therefore needed to ensure that the drug optimisation process is continued in order to improve outcomes and so that clinicians exercise caution when initiating new drugs before a patient’s condition has stabilised.
Secondary care is moving to use of SGLT2 inhibitors as part of first-line treatment of chronic HF, and evidence from SLGT2 inhibitor trials certainly supports their expedited use, with early separation of outcomes compared with placebo, which should encourage initiation of these drugs at the time of diagnosis. Among high-risk patients with diabetes, use of SGLT2 inhibitors as a first line therapy in place of metformin may require consultation with medicines management, as current guidance does not support their use without background metformin unless metformin is contraindicated or unsuitable.
Key points
After initial diagnosis and management of patients presenting to hospital with acute heart failure (HF), the heart failure team confirms the diagnosis; optimises existing therapies; and initiates new treatments to stabilise the condition, manage signs and symptoms, and reduce morbidity and mortality.
A suite of investigations and treatments is well established for HF with reduced ejection fraction, while options for HF with preserved ejection fraction have been limited.
Drugs such as angiotensin–neprilysin inhibitors; and repurposing of drugs developed for other conditions (eg, sodium-glucose co-transporter 2 inhibitors) increase the options for optimising the long-term management of patients with heart failure.
Approaches to identify deterioration between scheduled visits include annual electrocardiography and remote monitoring.
Questions remain around new tests, such as urinary sodium assessment in acute heart failure, how to achieve optimal diuresis; use of beta blockers in atrial fibrillation (AF) and higher normal ejection fraction; use of digoxin for rate control in patients with HF and AF; use of mineralocorticoid receptor antagonists beyond control of blood pressure in those with preserved ejection fraction; use of sacubitril–valsartan in patients with ejection fraction>40%; and by whom drugs should be managed after discharge.
Data availability statement
No data are available.
Ethics statements
Patient consent for publication
Ethics approval
Not applicable.
References
Footnotes
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Funding This initiative is sponsored by Boehringer-Ingelheim through the provision of an unrestricted educational grant. Boehringer-Ingelheim has had no influence over the content
Competing interests FZA has previously received a research grant funded by Medtronic. FZA has also received consultancy fees from AstraZeneca, Abbott, Medtronic, NovoNordisk, Pfizer, Pharmacosmos, Servier and Vifor. JB has received honoraria or consultation fees from Vifor, Novartis, Pharmacosmos, AstraZeneca, Boehringer Ingelheim and Eli Lilly.; AF has received honoraria or consultation fees from Astra-Zeneca, Boehringer-Ingelheim, Eli Lilly, Medtroinc, Edwards Scientific; BH has received honoraria from AstraZeneca; AJL has received honoraria or consultation fees from AstraZeneca; PP has received consultancy honoraria and/or sponsorship support from Boehringer Ingelheim, Pharmacosmos, Novartis, Vifor, AstraZeneca and Caption Health and research support from Bristol Myers Squibb in the past 5 years, not connected with this manuscript; HOS has received grants/research support from Abbott and honoraria or consultation fees from AstraZeneca and Novartis; CT has received honoraria or consultation fees from AstraZeneca, Bayer and Roche ; JGFC has received research grants and honoraria from Abbott, Amgen, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Medtronic, NI Medical, Pharmacosmos, Servier, and Vifor Pharma.
Provenance and peer review Commissioned; externally peer reviewed.