Yearly Archives: 2022

Heart failure care pathways: the power of collaboration and marginal gains

Br J Cardiol 2022;29:9–11doi:10.5837/bjc.2022.005 Leave a comment
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First published online January 26th 2022

Heart failure (HF) is increasingly common and incurs a substantial cost, both in terms of quality and length of life, but also in terms of societal and economic impact. While significant gains are being made in the therapeutic management of HF, we continue to diagnose most patients when they are acutely unwell in hospital, often with advanced disease.

This article presents our experience in working collaboratively with primary care colleagues to redesign our HF pathway with the aim of facilitating earlier, community, diagnosis of HF. In so doing, and, thus, starting prognostic therapy much earlier in the course of the disease, we seek to avoid both the cost of emergency hospitalisation and the cost of poorer outcomes.

Introduction

When COVID-19 struck, changing not only how we work as clinicians, but how patients wish their care to be managed, it provided the necessary impetus to undertake such transformation work. During the pandemic an estimated 23,000 diagnoses of heart failure (HF) were missed with an associated 44% drop in referrals for diagnostic echocardiography compared with 2019.1 During a six-week period of the second wave, another study found that there was a 41% decline in HF-related admissions and a 34% decline in heart attack admissions.2 Such reductions in admissions were seen during the first wave and were noted to contribute to more than 2,000 excess deaths during the pandemic peak in England and Wales.

Even before COVID-19, there had long been interest in transforming HF pathways in order to facilitate earlier diagnosis of this life-limiting and eminently treatable disease. We know that many patients are symptomatic for years prior to a diagnosis with HF, which occurs most often in hospital as opposed to in the community,3 and that such a ‘late’ diagnosis incurs significant costs, not only economic but societal too. While there has been some enthusiasm in transforming digital pathways to aid this, there lacked engagement from clinicians to undertake such service redesign.

The dual challenge of a growing HF burden and limited resources to manage this, have driven innovation and collaboration to enhance and improve existing pathways. We describe below our experience of transforming our local HF pathways.

Rationale for creating an ‘ideal’ HF pathway

In principle, most HF pathways are quite straightforward and are based on National Institute for Health and Care Excellence (NICE) guidelines – if there are symptoms and signs of HF, together with elevated natriuretic peptides, a GP can refer a patient for diagnostic echo and specialist review. However, HF is frequently comorbid and, even when it is not, symptoms can be missed if the diagnosis is not considered. Once considered, a GP needs to know, not only which tests to organise, but also how to do so within their constantly changing IT pathways. They then need to interpret the results based on the patient presentation and action these appropriately. As such, communication between specialist HF teams and primary care needs to be robust and clear, without additional unnecessary information and paperwork that can leave further requests and actions muddied. Coding is likewise essential for a number of reasons, not only to confirm quality and effectiveness, but also to ensure that patients have accurate medical records and are being treated and flagged appropriately. IT links with allied community teams tend to be obtuse, and pathways for advanced care planning, likewise, clunky. This all leads to multiple teams working disparately to treat the same patient.

An ideal HF pathway might, therefore, be expected to rely on sound clinical knowledge, signposting, communication, coding, IT literacy, and integration and joint working. Development of such a pathway requires involvement from all, including primary care, HF specialists, patients, IT and administrative input. In order to transform services, a project management team is essential to facilitate change, supporting and bringing together already overburdened clinical services; this is a resource rarely afforded to clinical teams.

Creating an integrated HF pathway in North West London

We focused our transformation work in one North West London (NWL) borough, concentrating initially on outcome measures for the pathways already in place, as well as the difficulties clinicians had in providing care. This area benefits already from a fully integrated HF service, with one named HF consultant and three Heart Failure Specialist Nurses (HFSNs), covering both the acute Trust and community HF services. The HF pathway was (and remains) a straightforward NICE-appropriate referral algorithm with specialist triage. The pathway benefits from using the same IT system with full interoperability within the community HF service and primary care – SystmOne (S1).

We found, perhaps unsurprisingly, that this borough faces many of the same challenges as the wider National Health Service (NHS): some HF referrals are not considered appropriate due to lack of relevant diagnostics and/or information (thus incurring delay), two-thirds of patients are diagnosed with HF in the acute setting as compared with the community, and only about 20% of HF patients, when compared with the expected prevalence for the area, had been seen by specialist HF services, likely due to poor coding. In addition, we estimated that up to 60% of HFSN time could be classified as administrative – nurses spent considerable time triaging inappropriate referrals due to lack of understanding, clarity of referral criteria and forms that were labour intensive to complete. The nursing templates on S1 did not integrate sufficiently with GP records and, thus, were not able to contribute to the generation of correct coding or appropriate documentation to support GPs, particularly on discharge for onward management. Lastly, the ability to refer to other community services via S1 was not available, and nurses had to refer outside of the patient record, not only increasing the administrative burden but creating potential risk of duplication and incorrect patient records.

In order to address these issues, a team was formed to map and then redesign the HF pathway from end to end. Two primary care physicians, one HF consultant and one HFSN were joined in weekly meetings by a project management team supported by Discover-NOW, the health research data hub led by Imperial College Health Partners.4 The ambition was to improve outcomes for HF patients by creating long-term, sustainable changes to the care pathway through the following objectives:

  1. The creation of a truly integrated HF pathway across primary and secondary care.
  2. Improvement of community HF referral rates and ensuring relevant data available.
  3. Reduction of non-elective HF admissions to secondary care.
  4. Improved efficiency of the HF services (maximising clinicians’ time).
  5. Improved HF patient experience and outcomes.
  6. Development of a novel and transferable approach for transforming other HF pathways.

Fundamental to this change was the need to bridge the divide between primary and secondary care – such integrated working was the only way to understand the patient journey from multiple perspectives. In addition to the core team, we also interviewed over 20 clinicians involved in the patient journey, including GPs, cardiologists, HFSNs, pharmacists, rapid response teams, district nurses and community matrons. Importantly, patient users were consulted on their experiences and areas for potential improvement. Using design-thinking methodology (whereby users are central to developing and creating ideas for transformation), a blueprint end-to-end pathway spanning first appointment with potential symptoms with the GP to end-of-life care was produced. This provided a valuable starting reference of what the patient journey might look like – of significance; this was the first time that all members of the team had a full perspective of all parts of the patient journey.

Demonstrating the cumulative impact of marginal gains in pathway transformation

We realised early on during this process that the original pathway was, in general, built on a sound premise. However, there were specific points that did not work as well as hoped and, although these issues were relatively minor, when added together, it became apparent that these amounted to significant breakdowns at various points in the pathway. We, therefore, chose to focus on the cumulative impact of making many small changes (marginal gains) to transform the pathway with the aim of making it more cohesive, clear and efficient.

Identifying opportunities

Table 1. Key pathway interventions

Organisational change
Improved communication channels between primary and secondary care – assigning HFSNs to PCNs
Increased involvement and role of pharmacists
Developed measurement frameworks to assess the ongoing impact of the changes made
SystmOne
New GP-specific referral template
Two new HF care plan templates – HFSNs and GPs
Four new clinic letters – GP referral, initial assessment, follow-up appointment and discharge letters
Redesigned HFSN templates with over 100 modifications
Integrated Coordinate My Care for advanced care planning
Technology
Implemented remote patient monitoring and uptitration technology/app
Over 25 HF education modules created for patients within the app
Digital version of HF and Patient Activation Measure questionnaires for patients to complete on tablet devices
Communication
Provided HFSN training to use new remote monitoring system
GP education webinar delivered to ~100 North West London GPs, including guidance on SGLT2 inhibitors
GP monthly virtual advice, guidance and education
Created comms assets to share our project achievements
Key: GP = general practitioner; HF = heart failure; HFSN = heart failure specialist nurse; PCN = primary care network; SGLT2 = sodium-glucose transport protein 2

With a forensic review of the pathway, the team initially identified over 30 such marginal gains opportunities across the HF pathway, with more identified as the project progressed. These were prioritised as either key opportunities and/or quick wins to deliver in 2020 to 2021, and were often dependent on the existing infrastructure, such as clinical systems, ordering mechanisms, and other community providers. Core categories of change are highlighted in table 1.

Specific examples of changes undertaken include:

  1. Generating new care plan templates that were more focused towards the information a busy GP needs to be aware of, separating this from the care plan that is sent to the patient.
  2. HFSN clinic templates were changed to make administrative duties more efficient and save time by allowing easier recording of clinical history and a smooth flow of information from the GP clinical system.
  3. The cardiology team are now able to make direct referrals to the various community services without the need for the GP. To enable this, quick links in S1 now exist to enable referral to community services (district nurses, community matrons, etc.) without needing to go outside the patient record.
  4. Weekly online educational sessions are held, which include time for GP advice and guidance, and which have helped improve relationships between colleagues.
  5. N-terminal pro-brain naturietic peptide (NT-proBNP) is now part of a ‘shortness of breath’ panel of tests that GPs can request, with BNP removed as an option. There is now guidance on use, and how to interpret the results, within S1/electronic patient record (EPR).
  6. A one-page referral proforma to secondary care now replaces the eight-page earlier version.
  7. A named nurse per primary care network (PCN) to help build relationships and collaboration. Offering education to all members of the primary care team and assisting with register reviews.

Interim data have shown clear benefits of having made many small changes to the pathway. We have seen a 7% indicative, appropriate, increase in referrals to the HF service; more than 300 new HF patient records have been created in six weeks using the new GP template; there have been over 100 newly coded HF patients per month since the launch of new templates. Lastly, we have also seen a 70% reduction in incorrect blood test requests, and we estimate 40 minutes per week in time saved for cardiologists from the new referral process. Data analysis is ongoing and further review at six months and one year expected. It is anticipated that such changes, as highlighted above, will lead to a significant cost reduction in HF spend, alongside a decrease in morbidity and mortality, relating to earlier and improved rates of diagnosis, these being more often undertaken in the community.

What’s next?

The blueprint of the HF pathway created by our team will work effectively for the next 12 months, but we have visualised more innovative and ambitious ideas for a future pathway within three to five years, in part based on current active research projects, which necessarily include technological and digital advances. However, this paper seeks to emphasise how success can result from building relationships across primary and secondary care – breaking down silo working and thinking – to uncover and ease previously unknown challenges from each side. This is the NHS working envisaged by patients, and which we, and many others, feel is necessary to tackle the increasing inequity and strain on our services.

Key messages

  • With growing burden of HF we must find innovative ways to utilise existing resources
  • Collaboration and integration across care settings is key to success in transforming and improving existing pathways
  • Marginal gains can lead to significant improvement

Conflicts of interest

CB has received educational honoraria from ViforPharma, Novartis, AstraZeneca and Alnylam; CMP has received educational honoraria from ViforPharma, Novartis and Medtronic; SG and AS: none declared.

Funding

The project management team were funded by AstraZeneca as part of the DiscoverNOW consortium.

Study approval

None required.

Acknowledgements

Jon Stephens, Hanna Pang, Lizzie Shupak, Ross Stone, Katrina Mullin and Manish Chatterjee, AstraZeneca UK.

References

1. Patel P, Thomas C, Quilter-Pinner H. Without skipping a beat. The case for better cardiovascular care after coronavirus. London: Institute for Public Policy Research, March 2021. Available from: https://www.ippr.org/files/2021-03/without-skipping-a-beat.pdf [accessed 14 June 2021].

2. Wu J, Mamas MA, Belder MA, Deanfield JE, Gale CP. Second decline in admissions with heart failure and myocardial infarction during the COVID-19 pandemic. J Am Coll Cardiol 2021;77:1141–3. https://doi.org/10.1016/j.jacc.2020.12.039

3. Bottle A, Kim D, Aylin P, Cowie MR, Majeed A, Hayhoe B. Routes to diagnosis of heart failure: observational study using linked data in England. Heart 2018;104:600–05. https://doi.org/10.1136/heartjnl-2017-312183

4. Imperial College Health Partners. Discover-NOW. Health data research hub for real world evidence. Available at: https://imperialcollegehealthpartners.com/discover-now/

Correspondence: Improving DVLA advice upon discharge after cardiac device implantation

Br J Cardiol 2022;29:40doi:10.5837/bjc.2022.006 Leave a comment
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Authors:
First published online January 26th 2022

Dear Sirs,

Implantation of cardiac devices is increasing at a tremendous rate. Rate of implantation of permanent pacemakers (PPM) alone is rising at a rate of 4.7% per decade.1 Implantation of these devices can transiently affect driving ability and, therefore, require temporary driving restrictions. It is a responsibility of the healthcare professionals to inform their patients of these restrictions to improve the safety of the patient and general public.2,3

Following the article by Drs Inderjeet Bharaj et al.4 asking whether the medical profession is doing enough to give patients appropriate advice about driving after certain cardiac conditions, we are writing to share our own protocol. Hereford County Hospital is a 208-bed district general hospital that implants around 200–250 cardiac devices yearly, including complex cardiac devices, such as implantable cardiac defibrillator (ICD) and cardiac resynchronisation therapy (CRT) devices. Many implants are in emergency inpatients and our aim was to increase the provision of appropriate driving advice upon discharge.

Method and measurements

Baseline data were collected for inpatient cardiac device implantation from 1 February 2020 until 30 April 2020. Patients were identified from the online hospital database. Electronic discharge summaries were reviewed to assess the provision of Driver and Vehicle Licensing Agency (DVLA) advice for the patients undergoing insertion of PPM, ICDs and CRT devices. An Excel spreadsheet was used to record the collected data. Patients who had outpatient day-case procedures were not included.

Plan, do, study, act (PDSA) cycle 1

Informal teaching was conducted for junior doctors and a standardised DVLA advice template (figures 1 and 2) was printed in the cardiology ward and coronary care unit. Information leaflets were handed out. This was followed by data collection until 31 May 2020.

Khalil - Figure 1. Standardised driving advice template provided at Hereford County Hospital: part 1
Figure 1. Standardised driving advice template provided at Hereford County Hospital: part 1
Khalil - Figure 2. Standardised driving advice template provided at Hereford County Hospital: part 2
Figure 2. Standardised driving advice template provided at Hereford County Hospital: part 2
PDSA cycle 2

Formal teaching was delivered to the junior doctors and an electronic version of the DVLA advice template was sent via email. Data collection was done until 30 June 2020.

PDSA cycle 3

Re-iteration of the importance of these guidelines among junior doctors by informal teaching and distribution of electronic versions to their mobiles for ease of access. Data collection was done at the end of July 2020.

PDSA cycle 4

Incorporation of the DVLA advice leaflet in the induction pack and formal teaching for the new batch of junior doctors. Data collection was completed on 31 August 2020.

Results

Baseline data revealed 29 patients underwent implantation of cardiac devices: six of them received driving advice upon discharge, i.e. 20.7%, and among them, four were in accordance with the DVLA guidelines.

After introduction of the standardised DVLA instruction template, we observed marked improvement in this percentage. Five of the six patients who underwent cardiac device implantation had appropriate written DVLA advice given upon discharge, i.e. 83.3%. In addition to the previous steps, measures taken in cycle 2 resulted in 100% compliance by the junior doctors and these were maintained in cycle 3 (n=8 for cycles 2 and 3).

In August, measures taken after induction of new doctors helped to maintain this percentage at 100%. All the five patients who had cardiac device implantation in August received correct driving advice upon discharge.

Discussion

Implantable cardiac devices improve survival of patients with risks of sudden cardiac death. However, these patients are still at risk of sudden incapacitation, which can pose risk to themselves and others. DVLA instructions for Group 1 and Group 2 licence holders, following insertion of a cardiac device, are to minimise these risks.2 This, however, is seldom re-iterated on discharge. Moreover, documentation of it is commonly lacking. Studies and quality improvement projects, focusing on provision of DVLA advice in acute coronary syndromes, have demonstrated similar results as well.4,5

We have found the introduction of measures like teaching, distribution of leaflets and formation of a standardised DVLA advice template to be helpful in improving this documentation. Moreover, the ease of access that the junior doctors get, with the availability of electronic copies over their phones, further helps it. Finally, a simple strategy like incorporation of these measures in the induction of new doctors helps to maintain sustainability.

These educational measures and simple strategies can be utilised in trusts across the UK to improve the quality of care being delivered to patients and promote patient safety.

Conflicts of interest

None declared.

Funding

None.

Study approval

Not required.

Arsalan Khalil
Internal Medicine Trainee

([email protected])

Tamara Naneishvili
Cardiology Registrar

Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham NHS Foundation Trust, Mindelsohn Way, Birmingham, B15 2GW

Abigail Mayo-Evans
Physician Associate

James Glancy
Cardiology Consultant

Hereford County Hospital, Wye Valley NHS Trust, Stonebow Road, Hereford, HR1 2ER

References

1. National Institute of Cardiovascular Outcomes Research (NICOR). National Audit of Cardiac Rhythm Management Devices: 2016/2017 Summary report. London: NICOR, 2019. Available from: https://www.nicor.org.uk/wp-content/uploads/2019/07/CRM-Report-2016-2017.pdf

2. Driver and Vehicle Licensing Agency (DVLA). Assessing fitness to drive: a guide for medical professionals. Swansea: DVLA, 2016. Available from: https://www.gov.uk/government/publications/assessing-fitness-to-drive-a-guide-for-medical-professionals

3. General Medical Council (GMC). Good medical practice. Manchester: GMC, 2013. Available from: https://www.gmc-uk.org/-/media/documents/good-medical-practice—english-20200128_pdf-51527435.pdf

4. Bharaj I, Sethi J, Bukhari S, Singh H. Driving after cardiac intervention: are we doing enough? Br J Cardiol 2021;28:19–21. https://doi.org/10.5837/bjc.2021.009

5. Naneishvili T, Khalil A, Mayo-Evans A, Glancy J. Improving DVLA advice provided to the patients with acute coronary syndrome upon discharge. Future Healthc J 2021;8:fhj.2020-0196. https://doi.org/10.7861/fhj.2020-0196

Freedom from failure: The British Society for Heart Failure Annual Meeting highlights

Br J Cardiol 2022;29:8 Leave a comment
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First published online January 12th 2022

This year’s 24th British Society for Heart Failure annual meeting successfully brought together experts in heart failure from all over the UK as well as keynote speaker and the Philip Poole-Wilson Memorial lecturer, Professor Milton Packer from the USA. This hybrid meeting, held in London in December 2021 at Queen Elizabeth II Exhibition Centre, welcomed a hugely diverse faculty including prominent figures in heart failure as well as key opinion leaders from the multidisciplinary heart failure team including nurses, cardiologists, pharmacists, elderly care physicians and patients living with heart failure. In contrast to many cardiovascular meetings, 44% of the British Society for Heart Failure (BSH) faculty were women. Dr Sarah Maria Birkhoelzer reports its highlights.

BSH Annual Meeting 2021

Heart failure as a neurohormonal disorder

Professor Milton Packer (Baylor University Medical Center, Dallas, Texas, USA) highlighted in the Philip Poole Wilson Memorial lecture the journey through heart failure (HF) research and how common, important and serious it is with more deaths from HF than all cancers combined.

The foundation of HF research is based on the view that it is a haemodynamic disease and, until 1970, diuretics were the prime focus of drug development. In the 1970s, vasodilator and inotropic drugs were developed to keep haemodynamic variables in the normal range and to stimulate cardiac contractility, which markedly improved cardiac performance. The fundamental holdback in the development of ground-breaking, disease-modifying drugs in HF was the paradigm that downregulation of activated renin-angiotensin system and sympathetic nervous system was contraindicated in HF.

The first landmark trials published in 1987 recognised HF as a neurohormonal disorder and demonstrated a reduction in hospitalisation and mortality with angiotensin-converting enzyme (ACE) inhibitors.1,2 From the late 1990s, beta blockers3–5 and mineral corticoid receptor antagonists6,7 were added to HF treatment. The spotlight subsequently moved to neprilysin inhibitors8 and sodium-dependent glucose cotransporters 2 (SGLT2) inhibitors, with combined SGLT 1 and 2 inhibitors now on the horizon.9 Table 1 summarises this journey.

Table 1. Pathophysiology of heart failure

Focus of heart failure care
Haemodynamic disease 1960s Diuretics
1970s Vasodilators and inotropes
Neurohormonal disease 1980s Angiotensin-converting enzyme (ACE) inhibitors
1990s Beta blockers
2000 Mineralocorticoid receptor anatagonists (MRAs)
2010 Angiotensin receptor-neprilysin Inhibitor (ARNI)
sodium-dependent glucose cotransporters 2 (SGLT2) inhibitors
2020 Combined SGLT1 and 2 inhibitors

Professor Packer highlighted the marked discrepancy between clinical trial results with advances in the outcomes of patients with HF and real-life settings in the community, highlighting regional changes and health inequalities. He pledges us to first translate these ground-breaking results into clinical practice before we aim to discover more treatment options.

New ESC guidelines: parallel instead of sequential initiation for four pillars of HF care

The sequential treatment therapy approach in HF guidelines originated from the order of clinical trial evidence delivered over the last 40 years (as highlighted by Professor Packer). Now the paradigm has shifted towards the initiation of all four HF drugs in parallel. Professor Teresa McDonagh (Kings College Hospital, London) presented the new European Society of Cardiology (ESC) guidelines on heart failure at the meeting, highlighting how as all four drugs are independently beneficial of each other within the first months of treatment, reaching the target dose of each individual medication now becomes secondary.

There is some concern that the discrepancy of National Institute for Health and Care Excellence (NICE) guidance in comparison to the new ESC guidance will impact, particularly for non-medical prescribers who take a huge role in optimising medical treatment in the community. Professor McDonagh drew attention to the fact that the new guidelines do not cover prevention or asymptomatic patients with left ventricular systolic dysfunction (LVSD) but focus on symptomatic HF with reduced ejection fraction (New York Heart Association [NYHA] II-IV). It is important to realise that patients with asymptomatic LVSD were not included in the trials examining SGLT2 inhibitors or angiotensin receptor-neprilysin Inhibitors (ARNIs). The question, however, remains, as to how asymptomatic HF is defined and what the role might be, for example, for cardio-pulmonary exercise testing or NT-proBNP, in this patient group (table 2).

Table 2. Outstanding questions

– How is asymptomatic heart failure defined?
– How should we treat asymptomatic patients with heart failure with reduced ejection raction (HFrEF)?
– How should we treat the elderly with HFrEF?
– Is NTproBNP under-utilised in the assessment of disease control?
– Does remote monitoring in heart failure reduce costs and improve outcomes?

Devices in heart failure

Professor Roy Gardner (Golden Jubilee Hospital, Clydebank) emphasised the importance of optimal medical therapy (OMT). Cardiac resynchronisation therapy (CRT) is recommended for symptomatic patients with HF of ischaemic aetiology: in sinus rhythm with a QRS duration ≥150 ms, a left bundle branch block (LBBB) QRS morphology, and a left ventricular ejection fraction (LVEF) of ≤35%, despite OMT, in order to improve symptoms and reduce morbidity and mortality (Class I, A recommendation, ESC HF guideline 2021). In non-ischaemic cardiomyopathy, he particularly encourages a wait beyond the recommended three months to allow potential recovery of the ejection fraction (EF) before considering a device. CRT does not reduce mortality or hospitalisation for HF in patients with HF and a QRS <130 ms10 (table 3).

Table 3. Univariate predictors of patient-reported severe pain

Downgraded to IIa recommendation Primary prevention implantable cardioverter defibrillators (ICDs) in patients with non-ischaemic cardiomyopathy
Level IIb, B Cardiac resynchronisation therapy (CRT) may be considered in non-left bundle branch block QRS
Class III, A ICD not recommended
– within 40 days of a myocardial infarction
– in New York Heart Association class IV heart failure with severe symptoms refractory to pharmacological therapy unless patients are candidates for CRT, a ventricular assist device (VAD), or cardiac transplantation

With the changing patient demographics in HF, as people live longer and the prevalence of HF increases in the elderly, the question arises of which age cut off should be considered for the primary prevention of implantable cardioverter defibrillators (ICDs), particularly when the average age of patients with non-ischaemic cardiomyopathy was 64 years in the landmark trial examining ICDs.11 It is important to highlight that older patients are at higher risk of mortality from other causes, hence the need for individualised decision making and risk assessment. Results from the ongoing RHYTHM-HF study are awaited to understand the role of arrhythmia in HF mortality.

Phenotyping in heart failure

Table 4. Phenotyping in heart failure

HF with reduced EF (HFrEF) HF with mildly reduced EF (HFmrEF) HF with preserved EF (HFpEF) Is there heart failure with supra-normal LVEF? (12)
LVEF 40% or less LVEF 41-49% LVEF 50% or more LVEF 65%

Professor Andrew Clark (Hull York Medical School) refers to HF as a condition that responds to HF treatment. The reason why HF phenotyping and subsequent treatment is affixed to LVEF is due to the wealth of evidence for patients with HFrEF (LVEF 40% or less). LVEF is a potent predictor of outcome with hospitalisation, cardiovascular death and all-cause death being significantly higher the lower the EF.12 The new ESC guidelines highlight the Level I evidence for HFrEF with limited evidence for patients with HF with mildly reduced EF (HFmrEF) (LVEF 41–49%) and no evidence for those patients with HF with preserved EF (HFpEF) (LVEF of 50% or more) or normal EF. However, what is normal ejection fraction,13 how do we measure it and what does it mean? It is not surprising that there is a degree of confusion when guidelines across the world have different ranges and nomenclature of EF (see table 5).

Table 5. Nomenclature used in guidelines

Nomenclature Range
Normal Ejection fraction (EF) of 50% and above
Moderately impaired/moderately abnormal/preserved EF range between 30-50%
Severely impaired/abnormal/reduced EF less than 40%

So how can we phenotype patients with HF better in the future? Should we use artificial intelligence14 and analysis of big data15 to guide the diagnosis of HF? Should a new phenotype characterised by supra-normal LVEF be considered as deviation of LVEF from 60% to 65% as it is associated with poorer survival?16

How can we co-create the digital future of heart failure?

Table 6. Outstanding questions in digital health

Will the use of digital health data…
– increase health care utilisation?
– add value to standard care?
– improve hard outcomes?
– increase health inequalities?

Table 7. Benefits of the using the Luscii app

– ongoing care of heart failure (HF) patients during the pandemic
– telephone consultations for up-titration of HF medication
– HF team to intervene if vital signs fall outside acceptable ranges
– increase clinic capacity by decreasing review time for each patient
– audit tool to assess HF team performance
– education of patients via app education modules

In the Journal of the American College of Cardiology Heart failure (JACC-HF) lecture, Professor Martin Cowie (National Heart and Lung Institute, Imperial College London) reminds us that the reason why we embrace digital technology in almost all aspects of life is because it is easier, more convenient and shows obvious benefit. Digital health should augment the work of healthcare professionals and help patients to live with their comorbidities in a more convenient way and support them in day-to-day life. The COVID-19 pandemic evolved into a ‘techcelleration’ (https://www.sciencedirect.com/science/article/pii/S2213177921005540) with a huge market of wearable technology available to deliver the digital future. One success story of digital medicine in HF, even before the pandemic, was the use of pulmonary artery pressure-guided therapy in ambulatory patients with HF (NYHA Class III) which was associated with fewer HF hospitalisations and improved quality of life.17 Early data suggest that digital medicine does not increase admission or mortality in patients with heart failure.18 Future work needs to be done to ensure health technology is more accessible and vulnerable and deprived groups won’t be disadvantaged (table 6).19

Dr Carla Plymen is leading the heart failure team at Imperial College Healthcare NHS Trust and is at the forefront of digital advances in HF care. Her team uses an app called Luscii which is a novel remote monitoring and education tool. It monitors patient’s vital signs, weight, quality of life and symptoms with Bluetooth connected blood pressure machine and scales. This allows the HF team to review vital signs and quality of life remotely. Results to demonstrate beneficial outcomes for patients are eagerly awaited (table 7).

The Cardiovascular disease prevention pathway (CPIP) and what does it mean for you

Dr Raj Thakkar (National Primary Care Cardiac Pathways Lead, NHS England) presented a multidisciplinary breathlessness pathway across primary and secondary care with the focus on the whole patient pathway. Evidence suggests that patients with breathlessness have repeated interactions with healthcare professionals with delayed diagnosis and management (table 8). The breathless pathway has been produced by ‘NHS RightCare’ to reduce variation and inequalities in practice and improve outcomes. It makes sure that the right person has the right care, in the right place, at the right time, making the best use of available resources. Initial investigations – beyond history and examination – should include an electrocardiogram/NT-proBNP, full blood count/thyroid function test/biochemistry, patient health questionnaire (PHQ4), GP physical activity questionnaire (GPPAQ), spirometry, and fractional exhaled nitric oxide. The overall aim of the new breathlessness pathway is to provide a comprehensive management plan within six months of presentation to the health service.

Table 8. Outcomes of the ‘breathless’ patient

– 50% of breathlessness in adults over 40 years of age is caused by heart failure (HF), chronic obstructive pulmonary disease (COPD), anaemia, anxiety or depression
COPD
– 58% of patients with COPD presented with respiratory symptoms for over five years prior to diagnosis20
HF
– 41% presented with HF symptoms in the five years prior to diagnosis.
– 79% were diagnosed during an acute admission to hospital21
Interstitial lung disease/ fibrosis
– 55% experienced misdiagnosis before the correct diagnosis was made22

Long COVID: STIMULATE CP Study

Dr Ami Banerjee (University College Hospital London) made us reconsider COVID-19 as a syndemic, a convergence of an infectious disease, under-treated non-communicable diseases and social determinants of health.23 With his background in epidemiology and big data he built a framework of a learning health system which is relevant to COVID-19 and HF. It aims to join up thinking between the silos of science, care and evidence to support the two million people in the UK that are estimated to have persistent symptoms for more than 12 weeks following COVID infection. As a result, 80 long COVID clinics have been established.

Dr Banerjee is co-principal investigator of the STIMULATE CP (Symptoms, Trajectory, Inequalities and Management: Understanding Long-COVID to Address and Transform Existing Integrated Care Pathway) study. To reduce the impact on patients, healthcare and economy, this study is trying to establish how to diagnose long COVID as well as aiming to understand how to manage Long COVID, including assessment of the outcomes of current clinical practice.

Culturally appropriate cardiac rehab and health care inequalities

Table 9. Coronary risk factors

Biological factors Genetic components
Psychosocial factors Social class and personality type
Behavioural factors Levels of physical activity and behaviours

Coronary risk factors can be divided into three groups: biological, psychological, and behavioural (table 9). Nikki Gardiner, Clinical Lead for Cardiac and Pulmonary Rehabilitation at University Hospital Leicester NHS Trust, presented the culturally tailored rehab programme, which is being carried out in Leicester, one of the most culturally and ethnically diverse cities in the UK. The programme was designed to challenge health inequalities and to reach ethnic minorities, particularly those from the South Asian community and women, to participate in cardiac rehab. As part of this programme, multilingual cardiac rehab assistants are being employed, who can interpret three different South Asian languages. Volunteer posts have been offered to past participants of the programme to assist with exercise classes. This more bespoke South Asian rehabilitation programme resulted in a 116% uptake for South Asian people attending cardiac rehab with a significant increase in women attending six months after the programme had started. Interestingly, this programme resulted in a higher proportion of women from Asian backgrounds participating than women from British backgrounds participating in the English-speaking classes.

Are cardiologists ageist: frailty and the heart

In the National Institute for Cardiovascular Outcomes Research (NICOR) 2019/2020 National Cardiac Audit Programme,  there was a significant decline in the prescription of disease-modifying drugs for patients with HFrEF with a marked reduction in patients above the age of 85 years. But even in patients over 55 years, there was an age-marked reduction in access to diagnostics, drugs and specialist care. How can we improve the care and outcomes of the elderly population?

Dr Patricia Cantley (Midlothian Frailty Project, Edinburgh) presented her work with hospital at home and end of life care for patients with HF. Hospital at home is a new concept to deal with the increased demand for bed-based hospital care (table 10). First trials suggest that acute care at home led by hospital specialists might be an alternative to hospitalisation for selected older persons.24

Table 10. Hospital at home

What is hospital at home? What is it not?
Medical care is led by hospital specialist Not early supportive discharge
Urgent access to hospital level diagnostics Not a virtual ward for chronic disease management
Acute complex conditions managed at home Early supported discharge
Short time limited acute episodes of care Outpatient anti-microbial team

New BSH board appointments 2021–2023

Chair Professor Roy Gardner
Past Chair Professor Simon Williams
Chair Elect Dr Lisa Anderson
Deputy Chair Ms Carys Barton
Treasurer Dr Sue Piper
Councillor Dr Patricia Campbell
Councillor Ms Margaret Simpson
Councillor Professor Zaheer Zousef
Nurse Forum Chair Ms Poppy Brooks

Future of heart failure research: Early Investigator Award

In the heart failure research workshops, the BSH is aiming to put a bigger emphasis on mentoring research in this area. The aim is to diversify the research community and promote novel ideas from outside the established research centres. It was therefore welcome that the Early Investigator Award – an opportunity open to BSH members (physicians in training, nurses and other professionals allied to medicine) to showcase their work – was, for the first time in history, awarded to all three finalists (table 11).

Table 11. The three finalists for the Early Investigator Award

BSH Member Location Topic
Dr Simon Beggs University of Glasgow A novel method to characterise cardiac rhythm at the time of death in patients with heart failure (RHYTHM-HF)
Rosalyn Austin Portsmouth Hospitals University NHS Trust Chronic heart failure SYMptoms imPACT on burden of treatment (SYMPACT): a mixed method observational study
Dr Amrit S Lota Royal Brompton Hospital, London;
National Heart & Lung Institute, Imperial College London		 Genetic architecture of acute myocarditis and the overlap with inherited cardiomyopathy

Sarah Birkhoelzer
Cardiology Registrar
Queen Alexandra Hospital, Portsmouth Hospitals University NHS Trust

References

1. Group CTS. Effects of enalapril on mortality in severe congestive heart failure. N Engl J Med 1987;316:1429–35.

2. Investigators S. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 1991;325:293–302.

3. Group M-HS. Effect of metoprolol CR/XL in chronic heart failure: metoprolol CR/XL randomised intervention trial in-congestive heart failure (MERIT-HF). The Lancet 1999;353:2001–7.

4. Krum H RE, Mohacsi P, Rouleau JL, et al. Effects of initiating carvedilol in patients with severe chronic heart failure: results from the COPERNICUS Study. JAMA 2003;289:712–8.

5. Poole-Wilson PA SK, Cleland JG, Di Lenarda A, et al. Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure in the Carvedilol Or Metoprolol European Trial (COMET): randomised controlled trial. Lancet 2003;362:7–13.

6. Zannad F MJ, Krum H, van Veldhuisen DJ, et al. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med 2011;364:11–21. https://doi.org/10.1056/NEJMoa1009492

7. Pitt B ZF, Remme WJ, Cody R, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med 1999;341:709–17.

8. McMurray JJ, Milton P, Desai AS, Gong J, et al. Angiotensin–neprilysin inhibition versus enalapril in heart failure. N Engl J Med 2014;11:993–1004. https://doi.org/10.1056/NEJMoa1409077

9. Bhatt DL SM, Steg PG, Cannon CP, et al. Sotagliflozin in patients with diabetes and recent worsening heart failure. N Engl J Med 2021;384:117–28. https://doi.org/10.1056/NEJMoa2030183

10. Ruschitzka F AW, Singh JP, Bax JJ et al. Cardiac-resynchronization therapy in heart failure with a narrow QRS complex. N Engl J Med 2013;369:1395–405. https://doi.org/10.1056/NEJMoa1306687

11. Køber L TJ, Nielsen JC, Haarbo J, et al. Defibrillator implantation in patients with nonischemic systolic heart failure. N Engl J Med 2016;375:1121–30. https://doi.org/10.1056/NEJMoa1608029

12. Lund LH, Claggett B, Liu J, Lam CS, 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. https://doi.org/10.1002/ejhf.1149

13. Hudson S PS. What is ‘normal’ left ventricular ejection fraction? Heart 2020;106:1445–6. http://doi.org/10.1136/heartjnl-2020-317604

14. Woolley RJ CD, Ouwerkerk W, Tromp J, et al. Machine learning based on biomarker profiles identifies distinct subgroups of heart failure with preserved ejection fraction. Eur J Heart Fail 2021;23:983–91. https://doi.org/10.1002/ejhf.2144

15. Uijl A SG, Vaartjes I, Dahlström U, et al. Identification of distinct phenotypic clusters in heart failure with preserved ejection fraction. Eur J Heart Fail 2021;23:973–82. https://doi.org/10.1002/ejhf.2169

16. Wehner GJ JL, Haggerty CM, Suever JD, et al. Routinely reported ejection fraction and mortality in clinical practice: where does the nadir of risk lie? Eur Heart J 2020;41:1249–57. https://doi.org/10.1093/eurheartj/ehz550

17. Angermann CE AB, Anker SD, Asselbergs FW, et al. Pulmonary artery pressure-guided therapy in ambulatory patients with symptomatic heart failure: the CardioMEMS European Monitoring Study for Heart Failure (MEMS-HF). Eur J Heart Fail 2020;22:1891–901. https://doi.org/10.1002/ejhf.1943

18. Sammour Y SJ, Austin A, Magalski A, et al. Outpatient management of heart failure during the COVID-19 pandemic after adoption of a telehealth model. JACC: Heart Failure 2021;9:916–24. https://doi.org/10.1016/j.jchf.2021.07.003

19. Reed M.E. HJ, Graetz I, et al. Patient characteristics associated with choosing a telemedicine visit vs office visit with the same primary care clinicians. JAMA Netw Open 2020(e205873). https://doi.org/10.1001/jamanetworkopen.2020.5873

20. Jones RC PD, Ryan D, Sims EJ, et al. Opportunities to diagnose chronic obstructive pulmonary disease in routine care in the UK: a retrospective study of a clinical cohort. Lancet Respir Med 2014;2:267–76. https://doi.org/10.1016/S2213-2600(14)70008-6

21. Bottle A KD, Aylin P, et al. Routes to diagnosis of heart failure: observational study using linked data in England. Heart 2018;104:600–5. http://doi.org/10.1136/openhrt-2018-000935

22. Cosgrove GP BP, Danese S, Lederer DJ. Barriers to timely diagnosis of interstitial lung disease in the real world: the INTENSITY survey. BMC Pulm Med 2018;18:9. https://doi.org/10.1186/s12890-017-0560-x

23. Horton R. Offline: COVID-19 is not a pandemic. Lancet 2020;396:874. https://doi.org/10.1016/S0140-6736(20)32000-6

24. Shepperd S BC, Cradduck-Bamford A, Ellis G, et al. Is comprehensive geriatric assessment admission avoidance hospital at home an alternative to hospital admission for older persons? Ann Intern Med 2021;174:889–98. https://doi.org/10.7326/M20-5688

New agents for DOAC reversal: a practical management review

Br J Cardiol 2022;29:26–30doi:10.5837/bjc.2022.001 Leave a comment
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Authors:
Sponsorship Statement: The development of this practical management review has been sponsored by Alexion Pharmaceuticals UK Limited.

First published online January 12th 2022

Bleeding is the commonest and most concerning adverse event associated with anticoagulants. Bleeding, depending on the severity, is managed in various ways, and for severe or life-threatening bleeding, specific antidotes are indicated and recommended. This review provides guidance relating to specific direct oral anticoagulant (DOAC) reversal agents, the antidotes. We discuss their indications for use, dosing, and potential side effects.

Introduction

New agents to reverse anticoagulation

Anticoagulation is utilised in the management of venous thromboembolism and to prevent thrombotic complications in patients with cardiac comorbidities, e.g. atrial fibrillation (AF), valvular heart disease, congenital heart disease, and other indications. Direct oral anticoagulants (DOACs), also known as NOACs (non-vitamin K antagonist oral anticoagulants), have shown superior efficacy, safety, adherence and tolerability over traditional anticoagulants, such as vitamin K antagonists and low-molecular weight heparins, and this has resulted in a paradigm shift with DOACs as the preferred options for most patients with thrombotic disorders.1-3

DOACs can be subclassified as inhibitors of clotting factor Xa (FXa) such as rivaroxaban, apixaban and edoxaban, and inhibitors of clotting factor IIa (FIIa) such as dabigatran etexilate. National Institute for Health and Care Excellence (NICE) guidance recommends DOACs (apixaban, edoxaban, rivaroxaban and dabigatran) for AF with a CHA2DS2-VASC score ≥2 and to consider anticoagulation with a score of 1.4 A vitamin K antagonist is advised if a DOAC is contraindicated or not tolerated, and, for those established on warfarin, a transition to a DOAC should be offered.

Similarly, for suspected venous thromboembolism (VTE), DOACs are initiated while awaiting a confirmatory scan, in preference to low-molecular-weight heparin, in the absence of any contraindication, and are the agent of choice for a confirmed VTE, including in cancer patients.5 Furthermore, DOACs are utilised in specific settings for prophylaxis during periods of particularly high risk, such as following orthopaedic surgery.6

Bleeding – incidence and risk factors

Bleeding is the primary risk with any anticoagulant therapy, but compared with traditional vitamin K antagonists (such as warfarin), the risk is generally thought to be lower with DOACs due to their shorter half-lives (ranging from 5 to 17 hours), more predictable pharmacokinetics, and reduced food/drug interactions. Superior safety outcomes were demonstrated in the DOAC versus vitamin K antagonist phase III trials in patients with non-valvular AF and VTE. The bleeding incidence varies according to the severity of bleeding (major, clinically relevant non-major or minor bleeding), the type of DOAC, the indication, and individual risk factors.

Bleeding incidence and mortality in trials and observational data

The risk of bleeding with DOACs in patients with AF (rates per 100 patient-years) versus vitamin K antagonists were compared in separate studies. These data showed a range for major bleeding of 1.6–3.6 versus 3.1–3.6; major plus clinically relevant non-major bleeding 4.1–20.1 versus 3.0–20.3; intracranial haemorrhage (ICH) 0.2–0.5 versus 0.7–0.9; and major gastrointestinal (GI) bleeding 0.8–3.2 versus 0.9–2.2. 7 The risk of major bleeding with oral anticoagulants in patients with VTE is 2% to 3% per year. In patients with VTE, after the first three months, bleeding rates per 100 patient-years for major bleeding are 2.7 and for ICH 0.65.8

Observational data in the UK have shown the standardised risk rate for major bleeding per 1,000 person-years is 21.8 for dabigatran, 26.5 for rivaroxaban and 15.4 for apixaban. The use of DOACs is increasing in the UK.9 For DOAC-related major bleeds, around 30% to 50% of bleeds occur in the GI tract, and around 10% to 25% of major bleeding events are ICHs.10-12 Mortality from major bleeding associated with DOAC use is 7.6% (vs. 11% on VKA).13 For DOACs, ICH-related 30-day mortality ranges from 45% to 48%.14,15

Bleeding risk scores have previously been developed for AF indications, such as HAS-BLED, ABC, ORBIT, ATRIA and HEMORR2HAGES. Other scores have been developed for VTE. A high score should trigger a review of the indication, risks and benefits, the duration of therapy in the VTE setting and addressing any modifiable factors to ameliorate bleeding risk.2 Risk factors can be classified into modifiable, potentially modifiable and non-modifiable.2 Most of the risk factors are more prevalent with increasing age. Routine monitoring of DOACs is not required in the same way that it is with vitamin K antagonists, but patients should be counselled regarding bleeding risk, including signs and symptoms of occult bleeding. Patients should be regularly examined for bleeding, anaemia and modifiable risk factors.

Modifiable bleeding risk factors

These include systemic hypertension (especially with systolic blood pressure >160 mmHg), alcohol excess (>8 units/week) and medications predisposing to bleeding, such as antiplatelet therapy, non-steroidal anti-inflammatory drugs (NSAIDs) and selective serotonin reuptake inhibitors (SSRIs). Antiplatelet agents are often used in combination with DOACs, usually in the setting of arterial vascular disease, such as acute coronary syndromes, and data show concomitant use escalates the bleeding risk and, hence, the risk–benefit needs to be assessed. Other medications, such as strong inhibitors of P-glycoprotein or CYP3A4 can potentiate DOAC levels and increase the risk of bleeding. These need to be reviewed before starting a DOAC, and carefully considered if commenced while on DOAC treatment, particularly if long-term anticoagulation is indicated.2

Potentially modifiable bleeding risk factors

Renal dysfunction increases bleeding risk, the greater the dysfunction the higher the bleeding risk (6.8% vs. 3.8% for moderate vs. mild), and worsening renal function is associated with higher drug concentrations due to poor excretion,12 the dosing of DOACs reflects this. Liver and platelet dysfunction, anaemia and very low body weight can also increase the bleeding risk, and DOAC levels should be considered in these patients.

Non-modifiable risk factors

Age is the most important non-modifiable risk factor associated with an increased risk of bleeding. Paradoxically, this category also benefits more from anticoagulation to prevent thrombotic complications. A prior history of bleeding, genetic factors, dialysis dependence/kidney transplant, previous stroke, liver cirrhosis and malignancy also increase the bleeding risk.2

Bleeding – classification

Defining the severity and extent of the bleed can help direct treatment, definitions are often subjective.

Mild bleeding includes most milder, often self-limiting presentations of epistaxis, ecchymosis, mucosal bleeding, menorrhagia and haematuria. Management consists of temporarily discontinuing the DOAC, using appropriate local measures to stop the bleeding, supportive care and ensuring haemodynamic stability.

Moderate bleeding is bleeding that will result in a clinical review usually requiring intervention and/or hospitalisation. Examples include bleeding from the upper and lower GI tract, the respiratory tract and the urogenital tracts that does not require transfusion and is not associated with significant anaemia. The DOAC should be stopped and supportive measures instituted such as haemodynamic support, volume replacement, specific interventions (e.g. endoscopic or surgical haemostasis) and maintaining diuresis.

Major bleeding. There are a number of definitions for major bleeding, varying in sensitivity. One of the most sensitive is the International Society on Thrombosis and Haemostasis (ISTH) definition of major bleeding:16

  • Fatal bleeding, and/or
  • Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intra-ocular, retroperitoneal, intra-articular or pericardial, or intramuscular with compartment syndrome, and/or
  • Bleeding causing a fall in haemoglobin level of 20 g/L (1.24 mmol/L) or more, leading to transfusion of two or more units of whole blood or red cells.

The DOAC should be stopped. Ideally the specific reversal agents are used, but if not available, then prothrombin complex concentrate (PCC) at 50 IU/kg (hospitals usually have a cap on dosing) should be given and haemodialysis should be considered for dabigatran.

Once the bleeding has stopped, the patient should be re-assessed for suitability of the DOAC and when to restart it. Patients experiencing DOAC-associated bleeding are also at increased risk of developing subsequent thrombotic events, with those experiencing ICH being most at risk. Often the changes/interruptions in antithrombotic treatment can contribute to this risk.

Management of bleeding

General measures

Table 1. Investigations for patients with moderate-to-severe direct oral anticoagulant (DOAC)-associated bleeding

Laboratory test Initial assessment Repeat after reversal
Creatinine & urea •
Ionised calcium • •
Liver function •
Full blood count • •
Prothrombin time (PT) • •
Activated partial thromboplastin time (APTT) • •
Dilute thrombin time (dTT) • •
DOAC level • •
Fibrinogen • •
Group and screen •

All DOAC-associated bleeding should be initially managed in the same way, after this, specific management depends on the severity of bleeding. DOACs have short half-lives, so a conservative approach only may be needed. The DOAC should be stopped, and the amount of DOAC onboard should be established by considering the dose, when it was last taken, the age of the patient, renal and liver function, along with considering other drugs and comorbidities, to establish the full bleeding potential.

A full set of bloods should be taken (table 1) at initial assessment along with a DOAC level, coagulation profile (activated partial thromboplastin time [APTT], prothrombin time [PT], fibrinogen) and a group and screen. Some of these blood tests will need to be repeated, dependent on the treatment the patient receives.17

The dilute thrombin time is useful in assessing how much dabigatran is onboard: if normal or measurable it suggests low levels of dabigatran. A dabigatran-calibrated assay is available in some hospitals. The APTT/PT are not very useful in determining the amount of FXa inhibitor, as their sensitivity depends on which reagents are used, so it is laboratory specific. DOAC-calibrated assays are now available in many institutions, and these give a good idea of how much anticoagulation is onboard. A coagulation profile is a useful baseline test to have, especially if the patient is going to receive a large amount of blood, and fresh frozen plasma/cryoprecipitate may need to be given later as part of the major haemorrhage protocol.

A basic life support approach of ABC (airway, breathing, circulation) with fluid resuscitation, blood transfusion, triggering of the major haemorrhage protocol, if needed, and attempting local haemostasis, for example applied pressure. Tranexamic acid should be given if appropriate. Removal of the oral anticoagulant with gastric lavage, oral charcoal (if <2 hours since ingestion) or dialysis for dabigatran can be considered. However, these methods are rarely used as DOACs are absorbed rapidly after oral administration, also now that idarucizumab is available, dialysis is uncommon and activated charcoal is rarely used.18 Activated charcoal can also make management of the airway difficult if endoscopy is needed as it can be emetogenic.

Investigations to determine the site/cause of bleeding should be undertaken and then endoscopic, surgical or radiological measures implemented to stop the bleeding at source. This should be running in parallel with haemostatic support and reversal of the DOAC, if needed.

Reversal agents and antidotes

Specific treatment depends on the severity of the bleeding and the DOAC. There are two specific reversal agents (antidotes) approved for reversal of a DOAC: idarucizumab is approved for reversal of the direct thrombin inhibitor dabigatran, and andexanet alfa is approved for reversal of the direct FXa inhibitors apixaban and rivaroxaban (table 2).18,19 There are currently no approved reversal agents for the other direct FXa inhibitors; edoxaban and betrixaban. LMWH can be reversed by protamine, which is a highly cationic peptide that binds unfractionated heparin completely or LMWH partially, to form a stable inactive salt pair that has no anticoagulant activity.

Table 2. Characteristics of specific DOAC antidotes

Andexanet alfa
(Ondexxya® ▼)19		 Idarucizumab
(Praxbind®)18
Reversal agent for Factor Xa (FXa) inhibitor (apixaban, rivaroxaban) Dabigatran
Mechanism
  • Recombinant inactive form of human FXa
  • Binds and sequesters FXa inhibitor molecules
  • Rapidly reduces anti-FXa activity
  • Humanised monoclonal antibody fragment
  • Binds dabigatran with high affinity and specificity
Trials ANNEXA-A and -R, ANNEXA-4 RE-VERSE AD
Dose Low dose: 400 mg (rate 30 mg/min) bolus and 4 mg/min for 120 mins infusion
High dose: 800 mg (rate 30 mg/min) bolus and 8 mg/min for 120 mins infusion		 5 g (2 vials of 2.5 g/50 ml) and second dose can be given if needed
Administration See tables 3 and 4 Intravenous infusion over 5–10 minutes or bolus injection
Indications Life-threatening or uncontrolled bleeding on apixaban or rivaroxaban Life-threatening or uncontrolled bleeding on dabigatran
Contraindications Hypersensitivity to ingredients or known allergic reaction to hamster proteins None
Storage Three-year storage if refrigerated (2–8°C), do not freeze Refrigerated (2–8°C), do not freeze. Can be kept at room temperature for 48 hours
Adverse reactions Infusion-related common, e.g. flushing, hot, urticaria, dizziness, headache, cough Hypersensitivity, e.g. rash, allergic reactions including anaphylaxis (very rare)
Safety* 10% thrombotic event within 30 days 4.8% thrombotic event within 30 days
Recommendations Accepted by SMC for life-threatening or uncontrolled bleeding
Recommended by NICE for life-threatening/uncontrolled GI bleeds. It is recommended only in research in ICH (ANNEXA-I trial) but not other major bleeds		 Accepted by SMC for life-threatening or uncontrolled bleeding
NHS cost £11,100 per pack (4 × 200 mg vials) £2,400 per 5 g (2 × 2.5 g/50 ml)
* The safety profile between andexanet alfa and idarucizumab is not directly comparable due to differing populations in the studies.
Key: GI = gastrointestinal; ICH = intracranial haemorrhage; NHS = National Health Service; NICE = National Institute for Health and Care Excellence; SMC = Scottish Medicines Consortium

Prothrombin concentrate complex (PCC)

PCC has been developed to contain highly concentrated coagulation factors (II, IX, X in three-factor [3-F] PCC and II, VII, IX and X in four-factor [4-F] PCC) to help replenish coagulation factor deficits in warfarin and haemophilia patients. However, the clinical trial evidence did not show an effect on important clinical outcomes to support their use for vitamin K antagonist-related bleeding. Sarode et al. compared 4-F PCC with plasma for urgent vitamin K antagonist reversal in bleeding patients and found there was no statistically significant difference in effective haemostasis between the two interventions. The only finding was that 4-F PCC did achieve international normalised ratio (INR) correction more rapidly than those in the plasma group.20

PCC have been used for DOAC-associated bleeding, in an off-label fashion, before the specific reversal agents appeared. They are now used if specific reversal agents are not available or if there is no specific reversal agent approved, such as with edoxaban. Their aim is to boost factor levels and, thereby, ‘overwhelm’ the inhibitors. However, they do not directly inhibit the DOAC, nor do they affect FXa levels.21 4F-PCC also do not reverse inhibition of thrombin generation (TG) by DOACs in therapeutic or supratherapeutic levels that are usually seen in DOAC-related bleeding. 4F-PCC are only able to normalise TG over a low and narrow range of FXa inhibitor concentrations (<75 ng/ml).22

Dabigatran reversal

Idarucizumab is a humanised monoclonal antigen binding fragment (Fab) antibody that binds dabigatran with 350 times more avidity than thrombin, and rapidly reverses its anticoagulant effect. It has no intrinsic activity in the coagulation system, providing immediate, complete and sustained reversal of the dabigatran effect.18

The patient is given a 5 g dose, given as two 50 ml bolus infusions of 2.5 g, no more than 15 minutes apart. Idarucizumab can re-enter the circulation from the extravascular space between 12 and 24 hours after reversal, so if a patient shows new/recurrent bleeding/needs further surgery with a prolonged clotting time, a further dose should be considered. No dose adjustment is required in the elderly, those with renal or hepatic impairment. There are no data on pregnant women or breast feeding.

It has been licensed by the European Medicines Agency (EMA) and Food and Drug Administration (FDA) in the USA for emergency surgery/urgent procedures, and in life-threatening or uncontrolled bleeding. Licensing was based on the phase III RE-VERSE AD (A Study of the RE-VERSal Effects of Idarucizumab on Active Dabigatran) trial.18 There were no serious adverse safety signals and at 90 days thromboembolic events occurred in 6.3% of patients reversed for haemorrhage and in 7.4% of those having emergency surgery. In the haemorrhage arm, greater than 90% of these complications occurred in patients who did not have re-initiation of their anticoagulant therapy.

Factor Xa inhibitor reversal

Andexanet alfa is the specific antidote for FXa inhibitors, apixaban and rivaroxaban, and is a truncated form of enzymatically inactive FXa. It is a recombinant protein that lacks the membrane-binding Y-carboxyglutamic acid (GLA) domain, so it has no biologic activity in the coagulation cascade. A mutation in the catalytic domain also removes its intrinsic procoagulant activity. It retains the ability of native FXa to bind direct and indirect FXa inhibitors and sequester them, thereby acting as a decoy to neutralise the anticoagulant effects of FXa inhibitors by preventing the inhibitors from binding endogenous FXa. As well as rapidly reducing anti-FXa activity, a measure of the anticoagulant effect of FXa inhibitors, it also reduces the unbound fraction of the plasma level of FXa inhibitor.19

The dose of andexanet alfa must be tailored to the molar concentration of the anticoagulant and an infusion must be maintained to continue the competitive blockade of the anticoagulant. As in the ANNEXA-4 (Andexanet Alfa, a Novel Antidote to the Anticoagulation Effects of Factor Xa Inhibitors) study, the bolus dose of andexanet alfa must be followed by a two-hour infusion to avoid rebound FXa activity.19 The recommended dosing of andexanet alfa depends on the specific FXa inhibitor, the dose of FXa inhibitor and the time since the patient’s last dose of FXa inhibitor (tables 3 and 4). The efficacy and safety of repeated administration of andexanet alfa after this has not been established.

Table 3. Summary of dosing reversal based on timing and size of last dose

Factor Xa inhibitor Last dose Timing of last dose before andexanet alfa initiation
<8 hours or unknown ≥8 hours
Apixaban ≤5 mg Low dose Low dose
>5 mg/unknown High dose
Rivaroxaban ≤10 mg Low dose Low dose
>10 mg/unknown High dose

Table 4. Dosing regimens for andexanet alfa

Initial intravenous bolus Continuous intravenous infusion Total number of 200 mg vials needed
Low dose 400 mg at a target rate of 30 mg/min 4 mg/min for 120 minutes (480 mg) 5
High dose 800 mg at a target rate of 30 mg/min 8 mg/min for 120 minutes (960 mg) 9

Andexanet alfa has been approved by the EMA and FDA for patients treated with apixaban or rivaroxaban, when reversal of anticoagulation is needed owing to life-threatening or uncontrolled bleeding. The EMA note there is not enough evidence on the use of andexanet alfa to reverse the effects of edoxaban, another FXa inhibitor. This licensing is based on a series of pivotal studies. ANNEXA-A and ANNEXA-R were studies to evaluate the safety and ability of andexanet alfa to reverse the anticoagulation effect of apixaban and rivaroxaban, respectively.23 The ANNEXA-4 study was the phase III study in patients with acute major bleeding. Andexanet alfa is not licensed prior to urgent surgery for reversal of anti-FXa inhibitors, however, a study is planned (ANNEXA-S). A further randomised-controlled trial of andexanet alfa versus standard care in ICH is currently being undertaken (ANNEXA-I).

No dose adjustment is needed for the elderly, renal or hepatic impairment. Hypersensitivity reactions are possible if the patient has a known allergic reaction to hamster proteins.

Conclusion

DOACs are the first-line option for anticoagulation in AF and VTE. DOACs have a favourable bleeding profile compared with vitamin K antagonists, but can nonetheless be associated with critical site major bleeding, uncontrolled bleeding requiring transfusion, and fatal bleeding. Andexanet alfa and idarucizumab are targeted reversal agents that can be used in life-threatening or uncontrolled bleeding with rivaroxaban/apixaban or dabigatran, respectively. They should be used in conjunction with general haemostatic measures and definitive management of the bleeding source. For non-clinically significant or non-major bleeding we do not advise use of either of these drugs. Clinicians involved in managing major haemorrhage should familiarise themselves with storage locations and administration of both reversal drugs.

Key messages

  • Direct oral anticoagulants (DOACs) are the first-line option for anticoagulation in atrial fibrillation (AF) and venous thromboembolism (VTE)
  • While DOACs have a favourable bleeding profile compared with vitamin K antagonists, they can be associated with major bleeding events
  • Andexanet alfa and idarucizumab are targeted reversal agents that can be used in life-threatening or uncontrolled bleeding with rivaroxaban/apixaban or dabigatran, respectively
  • They should be used in conjunction with general haemostatic measures and definitive management of the bleeding source

Conflicts of interest

ATC has received research support from Alexion Pharmaceuticals, Bayer, Boehringer Ingelheim, Bristol-Myers-Squibb, Daiichi-Sankyo, Johnson & Johnson, Pfizer, Portola Pharmaceuticals, and Sanofi. He has received consultancy fees and/or honoraria from Abbott, AbbVie, ACI Clinical, Alexion Pharmaceuticals, Aplagon, Aspen, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol-Myers Squibb, BTG, Daiichi-Sankyo, EmstoPA Ltd, EPG Health, GLG, Guidepoint Global Gulf Coast Developments, Janssen, Johnson & Johnson, JP Morgan, Leo Pharma, Lifesciences Consulting, McKinsey, Medscape, Navigant, Northstar Communications, Ono, Pfizer, Portola Pharmaceuticals, Sanofi, Temasak Capital, Total CME, TRN, and Windrose Consulting Group. KW and UF: none declared.

Funding

The development of this practical management review has been sponsored by Alexion Pharmaceuticals UK Limited.

References

1. Ruff CT, Giugliano RP, Braunwald E et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet 2014;383:955–62. https://doi.org/10.1016/S0140-6736(13)62343-0

2. Steffel J, Verhamme P, Potpara TS et al. The 2018 European Heart Rhythm Association practical guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation. Eur Heart J 2018;39:1330–93. https://doi.org/10.1093/eurheartj/ehy136

3. van Es N, Coppens M, Schulman S, Middeldorp S, Buller HR. Direct oral anticoagulants compared with vitamin K antagonists for acute venous thromboembolism: evidence from phase 3 trials. Blood 2014;124:1968–75. https://doi.org/10.1182/blood-2014-04-571232

4. National Institute for Health and Care Excellence. Atrial fibrillation: diagnosis and management. NG196. London: NICE, 2021. Available from: https://www.nice.org.uk/guidance/ng196

5. National Institute for Health and Care Excellence. Venous thromboembolic diseases: diagnosis, management, and thrombophilia testing. NG158. London: NICE, 2020. Available from: https://www.nice.org.uk/guidance/ng158

6. National Institute for Health and Care Excellence. Venous thromboembolism in over 16s: reducing the risk of hospital-acquired deep vein thrombosis or pulmonary embolism. NG89. London: NICE, 2019. Available from: https://www.nice.org.uk/guidance/ng89

7. Niessner A, Tamargo J, Morais J et al. Reversal strategies for non-vitamin K antagonist oral anticoagulants: a critical appraisal of available evidence and recommendations for clinical management – a joint position paper of the European Society of Cardiology Working Group on Cardiovascular Pharmacotherapy and European Society of Cardiology Working Group on Thrombosis. Eur Heart J 2017;38:1710–16. https://doi.org/10.1093/eurheartj/ehv676

8. Linkins LA, Choi PT, Douketis JD. Clinical impact of bleeding in patients taking oral anticoagulant therapy for venous thromboembolism: a meta-analysis. Ann Intern Med 2003;139:893–900. https://doi.org/10.7326/0003-4819-139-11-200312020-00007

9. Loo SY, Dell’Aniello S, Huiart L, Renoux C. Trends in the prescription of novel oral anticoagulants in UK primary care. Br J Clin Pharmacol 2017;83:2096–106. https://doi.org/10.1111/bcp.13299

10. Giugliano RP, Ruff CT, Wiviott SD et al. Mortality in patients with atrial fibrillation randomized to edoxaban or warfarin: insights from the ENGAGE AF-TIMI 48 trial. Am J Med 2016;129:850.e2–857.e2. https://doi.org/10.1016/j.amjmed.2016.02.028

11. Green L, Tan J, Antoniou S et al. Haematological management of major bleeding associated with direct oral anticoagulants – UK experience. Br J Haematol 2019;185:514–22. https://doi.org/10.1111/bjh.15808

12. Beyer-Westendorf J, Forster K, Pannach S et al. Rates, management, and outcome of rivaroxaban bleeding in daily care: results from the Dresden NOAC registry. Blood 2014;124:955–62. https://doi.org/10.1182/blood-2014-03-563577

13. Chai-Adisaksopha C, Hillis C, Isayama T, Lim W, Iorio A, Crowther M. Mortality outcomes in patients receiving direct oral anticoagulants: a systematic review and meta-analysis of randomized controlled trials. J Thromb Haemost 2015;13:2012–20. https://doi.org/10.1111/jth.13139

14. Kessler CM, Goldstein JN. A new strategy for uncontrollable bleeding after treatment with rivaroxaban or apixaban. Clin Adv Hematol Oncol 2019;17(suppl 15):1–20. Available from: https://www.hematologyandoncology.net/supplements/a-new-strategy-for-uncontrollable-bleeding-after-treatment-with-rivaroxaban-or-apixaban/

15. Held C, Hylek EM, Alexander JH et al. Clinical outcomes and management associated with major bleeding in patients with atrial fibrillation treated with apixaban or warfarin: insights from the ARISTOTLE trial. Eur Heart J 2015;36:1264–72. https://doi.org/10.1093/eurheartj/ehu463

16. Schulman S, Kearon C, Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost 2005;3:692–4. https://doi.org/10.1111/j.1538-7836.2005.01204.x

17. Kaide CG, Gulseth MP. Current strategies for the management of bleeding associated with direct oral anticoagulants and a review of investigational reversal agents. J Emerg Med 2020;58:217–33. https://doi.org/10.1016/j.jemermed.2019.10.011

18. Pollack CV Jr, Reilly PA, van Ryn J et al. Idarucizumab for dabigatran reversal – full cohort analysis. N Engl J Med 2017;377:431–41. https://doi.org/10.1056/NEJMoa1707278

19. Connolly SJ, Crowther M, Eikelboom JW et al. Full study report of andexanet alfa for bleeding associated with factor Xa inhibitors. N Engl J Med 2019;380:1326–35. https://doi.org/10.1056/NEJMoa1814051

20. Sarode R, Milling TJ Jr, Refaai MA et al. Efficacy and safety of a 4-factor prothrombin complex concentrate in patients on vitamin K antagonists presenting with major bleeding: a randomized, plasma-controlled, phase IIIb study. Circulation 2013;128:1234–43. https://doi.org/10.1161/CIRCULATIONAHA.113.002283

21. Dzik WH. Reversal of oral factor Xa inhibitors by prothrombin complex concentrates: a re-appraisal. J Thromb Haemost 2015;13(suppl 1):S187–S194. https://doi.org/10.1111/jth.12949

22. Lu G, Lin J, Bui K, Curnutte JT, Conley PB. Andexanet versus prothrombin complex concentrates: differences in reversal of factor Xa inhibitors in in vitro thrombin generation. Res Pract Thromb Haemost 2020;4:1282–94. https://doi.org/10.1002/rth2.12418

23. Siegal DM, Curnutte JT, Connolly SJ et al. Andexanet alfa for the reversal of factor Xa inhibitor activity. N Engl J Med 2015;373:2413–24. https://doi.org/10.1056/NEJMoa1510991

Foundational drugs for HFrEF: the growing evidence for a rapid sequencing strategy

Br J Cardiol 2022;29:12–15doi:10.5837/bjc.2022.002 Leave a comment
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Authors:
Sponsorship Statement: AstraZeneca has provided a sponsorship grant towards this independent programme.

First published online January 12th 2022

In randomised, placebo- or active-controlled trials in patients with heart failure with reduced ejection fraction (HFrEF), each of the combination of a neprilysin inhibitor and an angiotensin-receptor blocker (i.e. sacubitril/valsartan), a beta blocker, a mineralocorticoid-receptor antagonist and a sodium-glucose co-transporter 2 (SGLT2) inhibitor have been shown to reduce morbidity and mortality, firmly establishing the role of these five agents, prescribed as four pills, as foundational therapy for HFrEF. Traditionally, the guideline-advocated strategy for the initiation of these therapies was based on the historical order in which the landmark clinical trials were performed, and the requirement to up-titrate each individual drug to the target dose (or maximally tolerated dose below this) prior to initiation of another therapy. This process could take six months or more to complete, during which time patients would not be taking one or more of these life-saving drugs. Recently an alternative, evidence-based, rapid three-step sequencing strategy has been proposed with the aim of establishing HFrEF patients on low-doses of all four foundational treatments within four weeks. This strategy is based on the premise that the benefits of each of these therapies are independent and additive to the others, the benefits are apparent at low doses early following initiation, and a specific ordering of therapies may increase likelihood of tolerance of others. This article will outline this novel rapid-sequencing strategy and provide an evidence-based framework to support its adoption into clinical practice.

Introduction

Rapid sequencing strategy for foundational HFrEF

To date, five pharmacological approaches have been demonstrated to significantly reduce the risk of mortality and prevent hospitalisation for worsening heart failure (HF) in patients with HF with reduced ejection fraction (HFrEF): the combination of a neprilysin inhibitor and an angiotensin-receptor blocker (i.e. sacubitril/valsartan), a beta blocker, a mineralocorticoid-receptor antagonist (MRA) and a sodium-glucose co-transporter 2 (SGLT2) inhibitor. Hereafter, these five agents, which can be prescribed as four pills, will be referred to as the ‘four foundational therapies for HFrEF’.1-11 The combination of these four therapies has been shown to provide clinically meaningful gains in survival free from worsening HF and prolong life-expectancy in patients with HFrEF.12 Until recently, based on the order in which the landmark trials demonstrating the benefit of these drugs were performed, the guideline-advocated approach when initiating these therapies was to introduce one treatment at a time in the order in which they were studied in clinical trials. Moreover, each new drug was only added when the dose of the prior therapy had been up-titrated to the dose shown to be efficacious in the relevant trials (or maximally tolerated dose below that).13,14 In practice, this would mean starting with an angiotensin-converting enzyme (ACE) inhibitor (or angiotensin-receptor blocker [ARB]) and up-titrating to the target dose, then adding a beta blocker and up-titrating the dose, followed by a MRA, a neprilysin inhibitor (added by switching from an ACE inhibitor or ARB) and, finally, an SGLT2 inhibitor. In most patients, this process could take six months or more to complete, during which they would not be taking one or more of these life-saving drugs for much of the time. In a challenge to this widely accepted paradigm, it has been recently suggested that a novel rapid-sequencing strategy should be adopted in which the aim should be to establish patients on low doses of each of the four foundational treatments within four weeks of initiation.15,16 This alternative strategy means that patients are exposed to the individual additive benefits of each class of drug, which are evident within weeks of starting, even at the initiating or sub-target dose. This article will outline this novel rapid-sequencing strategy and provide evidence to support its adoption into clinical practice.

Foundational therapy for HFrEF

Each of the four foundational pharmacological therapies for HFrEF has been shown in large, randomised, placebo- or active-controlled trials to reduce the risk of cardiovascular and/or all-cause mortality, and the risk of hospitalisation for worsening HF.1-11 These benefits have been demonstrated in two or more trials (i.e. providing external validity) or, in the case of sacubitril/valsartan, in one trial with a degree of statistical significance (p<0.00125) that is equivalent to that of at least two individual confirmatory trials. Furthermore, many of these treatments have been shown to have similar benefits in reducing mortality and the development of chronic HF in patients with left ventricular systolic dysfunction and/or HF at the time of acute myocardial infarction, a common pathological precursor to the development of HFrEF.17-22

Along with the four foundational treatments for HFrEF, other medications, including digoxin, ivabradine, vericiguat, omecamtiv mecarbil and the combination of hydralazine and isosorbide dinitrate, are considered second-line therapies. Indeed, in the recently updated European Society of Cardiology (ESC) guidelines for the management of HF, each of these medications are given a class II indication.23 Reasons for this weaker indication (rather than a class I indication as for the four foundational treatments) include a relatively small treatment effect, an effect on HF hospitalisation with no accompanying cardiovascular mortality benefit, or the suggestion of benefit only in certain subgroups of HFrEF patients.

Conventional sequencing of foundational drugs for HFrEF

Until recently, international guidelines for the management of HFrEF advocated a stepwise sequencing strategy when establishing patients on foundational HFrEF treatments.13,14 The recommended order of therapy initiation (renin–angiotensin system [RAS] inhibitor and beta blocker, followed by a MRA, a neprilysin inhibitor and a SGLT2 inhibitor) was based, not on clinical trial evidence supporting that order, but simply on the historical sequence in which the landmark evidence-generating trials were conducted. This strategy assumes, incorrectly, that the treatments studied earlier are more efficacious (and their initiation be prioritised) than those discovered more recently. This can be challenged by the observation that the use of digitalis, taken by >90% of patients at baseline in CONSENSUS (Cooperative North Scandinavian Enalapril Survival Study), has significantly declined and is no longer considered as a foundational treatment for HFrEF based on the results of the Digitalis Investigation Group (DIG) trial.24

A second aspect of the conventional approach was prioritising the up-titration of the dose of each individual drug class to the target dose (or maximally tolerated dose below that) before adding a new medication. During this process, the delay in initiating all four life-saving treatments potentially results in unnecessary hospitalisations and deaths.

The assumption that the recommended drug classes do not exert their benefits until they are up-titrated to maximum doses is contrary to the body of evidence demonstrating that low or starting doses of ACE inhibitors, beta blockers, MRAs and sacubitril/valsartan provide protection from death and reduce the risk of worsening HF. Indeed, each of the four classes of foundational therapies has been shown to exert their benefit within 30 days of initiation (i.e. when the patients were taking a low dose or before any up-titration).25-29 Furthermore, the additive benefits of the dose up-titration of a drug are relatively modest and limited to a reduction in the risk of hospitalisation compared with the benefits of adding a new medication; in the Assessment of Treatment with Lisinopril and Survival (ATLAS) and Heart failure Endpoint evaluation of Angiotensin II Antagonist Losartan (HEAAL) trials, a three- to seven-fold higher dose of a RAS inhibitor did not confer a mortality benefit, unlike the addition of a beta blocker, a MRA, a neprilysin inhibitor or a SGLT2 inhibitor in their respective landmark trials.30,31

Finally, the conventional strategy is based on the assumption that the benefits of new therapies were demonstrated in landmark trials when given to patients who were taking all other background therapies at the maximal dose, therefore, mandating this as a prerequisite before adding in any new medication. We know this not to be the case, as a significant proportion of patients in the randomised-controlled trials detailed above were not on the maximum doses of background therapy when each new additional foundational treatment was studied.32,33 Furthermore, not all patients in PARADIGM-HF (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) were taking a MRA and a relatively small proportion of patients in the SGLT2 inhibitor trials were taking a neprilysin inhibitor.9-11 By examining the totality of evidence (figure 1) it is quite clear that the benefits of each foundational drug class are independent and additive to the others, i.e. the benefit of each foundational therapy is not contingent on the patient taking the other treatments at target doses. This is perhaps no surprise given that each drug class has a distinct mechanism of action; RAS inhibitors, beta blockers and MRA independently antagonise the maladaptive neurohumoral activation that occurs in HF, neprilysin inhibitors augment endogenous levels of vasoactive peptides, including the natriuretic peptides, and SGLT2 inhibitors have a wide range of proposed mechanisms of action.34,35 A further limitation of the conventional strategy described, is that it is both time and labour intensive, requiring multiple clinic visits. This may explain why, despite a wealth of evidence supporting their benefits, few patients either receive or are on maximally tolerated doses of all four foundational therapies.36,37

Docherty - Figure 1. Evidence for the independent benefits of foundational drugs for heart failure with reduced ejection fraction (HFrEF)
Figure 1. Evidence for the independent benefits of foundational drugs for heart failure with reduced ejection fraction (HFrEF)

Proposed new rapid-sequencing strategy

A novel sequencing strategy (figure 2) has recently been proposed that aims to establish patients with HFrEF on all four foundational guideline-recommended treatments within 30 days.15,16 This proposal is based on a series of evidence-based principles. First, that the order of therapy initiation should not be dictated by historical precedent but rather by factors including the magnitude of reduction in risk of mortality and the ability of one treatment to enhance the tolerability and safety of others. Second, that the foundational treatments exert clinically important benefits early following initiation, and when taken at a low dose. Third, a previously commenced treatment does not require to be up-titrated to the target dose before initiation of subsequent therapies, as the additive benefit provided by dose up-titration is not greater (and may even be less) than that of the addition of a new medication. Finally, that the benefit of each treatment is independent and additive to that of the others.

Docherty - Figure 2. Conventional and rapid sequencing of foundational drugs
Figure 2. Conventional and rapid sequencing of foundational drugs16

Based on these underlying principles, the proposed new rapid-sequencing strategy suggests a three-step process aiming to achieve the target of all four foundational treatments initiated within four weeks, with further dose up-titration occurring after this. In other words, starting all four treatments is prioritised over the up-titration of any single treatment.

Step 1

Initiation of a low dose of an evidence-based beta blocker (bisoprolol, metoprolol succinate or carvedilol) along with a SGLT2 inhibitor (dapagliflozin or empagliflozin) in patients who are assessed to be clinically euvolaemic. Beta blockers are suggested as one of the two first-line medications due to the early and large magnitude of benefit in reducing the risk of sudden death.27 The CIBIS (Cardiac Insufficiency Bisoprolol Study) III trial, which reported that initiation of treatment with a beta blocker was safe and non-inferior to initiation of an ACE inhibitor, provides support to this strategy.38 CIBIS III also provides a rationale for combining a beta blocker and a SGLT2 inhibitor as the first step in the algorithm; the increased risk of non-fatal HF hospitalisation seen early after initiation of a beta blocker in CIBIS III may be offset by the substantial effect that SGLT2 inhibitors have in reducing the risk of worsening HF, as well as SGLT2 inhibitor’s potential short-term diuretic effect.39,40 A further, attractive benefit of the early initiation of a SGLT2 inhibitor is their renoprotective effect in attenuating the decline in renal function over time, which is seen in patients with HF.11,41

Step 2

Initiation of a combined ARB/neprilysin inhibitor in the form of sacubitril/valsartan, one to two weeks following Step 1. Sacubitril/valsartan has an additive effect to RAS inhibition alone, with a comparable effect on reducing the risk of mortality to beta blockers, and a significant effect on both major modes of death in HFrEF, death from progressive HF and sudden cardiac death.9,42 Furthermore, compared with an ACE inhibitor alone, sacubitril/valsartan attenuates the decline in renal function over time; this, along with the observation that both sacubitril/valsartan and SGLT2 inhibitors reduce the risk of hyperkalaemia and increase tolerance of a MRA, means that establishing patients on both of these medications may increase the subsequent likelihood of safely introducing and maintaining a patient on a MRA.43-45 In a subset of patients with low systolic blood pressure (<100 mmHg), tolerance with regards to hypotension can be first assessed with a low dose of an ARB with the addition of a neprilysin inhibitor once tolerance is established (a test of an ARB is preferred to an ACE inhibitor as the latter requires a minimum 36-hour washout before starting sacubitril/valsartan to minimise the risk of angioedema). Early hypotensive effects frequently resolve with repeated dosing and may sometimes require de-escalation of diuretic therapy.46

Step 3

Introduction of a MRA a further one to two weeks following Step 2 providing that updated renal function and serum potassium measurements are within the acceptable limits for commencing a MRA, i.e. potassium ≤5.0 mmol/L and estimated glomerular filtration rate (eGFR) ≥30 ml/min/1.73 m2. The initiation of a MRA once patients are established on a neprilysin inhibitor and a SGLT2 inhibitor is expected to increase the likelihood of tolerance, for the reasons detailed above, regarding attenuation of worsening renal function and the risk of hyperkalaemia (both of which can be exacerbated by a MRA). In select patients in whom Step 2 consists of adding a neprilysin inhibitor to a longstanding RAS inhibitor, then Steps 2 and 3 can be consolidated into a single step as the initiation of a neprilysin inhibitor and a MRA at the same time is not expected to result in an increase in adverse effects in patients who are already established on a RAS inhibitor. Furthermore, in patients who have difficulties with symptomatic hypotension, Step 2 and Step 3 can be reversed (i.e. a MRA introduced before a neprilysin inhibitor).

Following the completion of these three steps, the four foundational drugs should be up-titrated to the target doses studied in clinical trials or the maximally tolerated dose below (this does not apply to SGLT2 inhibitors as these are used in a single dose and do not require titration).

Conclusion

There is now unequivocal evidence that an ARB/neprilysin inhibitor, a beta blocker, a MRA and a SGLT2 inhibitor should be considered as foundational treatments for HFrEF. Each of these four drug classes provides independent and additive benefits to the others, which are realised early following the initiation of treatment. The onus is now on members of the HF multi-disciplinary team to ensure rapid and safe implementation of these four foundational HFrEF treatments. Although the evidence-based strategy described above may not be possible in all patients, it can be employed in many, and has the potential to prolong survival, prevent hospitalisations, reduce symptom burden, and improve quality of life.

Key messages

  • The foundational pharmacological treatments for heart failure with reduced ejection fraction (HFrEF) consist of the combination of a neprilysin inhibitor and an angiotensin-receptor blocker, i.e. sacubitril/valsartan, a beta blocker, a mineralocorticoid-receptor antagonist (MRA) and a sodium-glucose co-transporter 2 (SGLT2) inhibitor, i.e. five agents given in four tablets
  • Each of these therapies offers independent and additive benefits in reducing the risk of death and hospitalisation for heart failure, which are realised early following initiation of therapy and at low doses
  • During the initiation of these treatments we should, therefore, prioritise establishing patients on low doses of all four foundational treatments within four weeks rather than the traditional sequencing strategy of starting each individual medication and up-titrating to maximally tolerated/target dose prior to adding a new therapy

Conflicts of interest

KFD has received personal lecture fees from AstraZeneca and his employer, the University of Glasgow, has received payment from AstraZeneca for his work on the DAPA-HF trial. JJVM is supported by a British Heart Foundation Centre of Research Excellence Grant RE/18/6/34217; his employer, Glasgow University, has received payment for his work on clinical trials, consulting, and other activities from Alnylam, Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Cardurion, Cytokinetics, GlaxoSmithKline, Novartis, Pfizer, Theracos; and he has received personal lecture fees from the Corpus, Abbott, Hickma, Sun Pharmaceuticals, and Medscape.

Funding

AstraZeneca has provided a sponsorship grant towards this independent programme.

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