The NHS Long Term Plan (LTP) is a far reaching, ambitious strategy with significant implications for clinicians treating heart failure. At a meeting for physicians, GPs, specialist nurses and pharmacists, speakers showed how implementation of NICE guidance, optimisation of the patient experience and latest advances in heart failure management can help achieve the Plan’s key aims for the NHS.
The LTP’s priorities for primary and secondary prevention of cardiovascular disease (CVD), cardiac rehabilitation and rapid access to specialist care for patients with heart failure (HF) are good news for clinicians.1 But the emphasis on echocardiography instead of NT-proBNP testing in primary care is disappointing and the 33% target for same-day emergency care will challenge hard pressed HF services unable to achieve the current 20% target for patients with acute HF.
These were the conclusions of Dr Lisa Anderson, Heart Failure Consultant at St George’s, University of London in the opening presentation of the meeting. Yet, despite, the Plan’s deficiencies she urged delegates to embrace its forward-thinking aspects.
“The Long Term Plan is well thought out, especially for primary and secondary prevention and previously neglected aspects including cardiac rehabilitation and heart failure. We should also welcome the move to Integrated Care Systems that bring together NHS and voluntary services as these will be important to end-of-life care for our patients,” she said.
Dr Anderson explained that designated funding is being provided for the conversion of Clinical Commissioning Groups (CCG) to Integrated Care Systems. There will also be targeted funding for improved access to cardiac rehabilitation, personalised care, prevention teams in the community and echo pilots (but not for NT-proBNP testing).
Data from the recent National Confidential Enquiry into Patient Outcome and Death (NCEPOD) for patients who died in hospital following an admission for acute HF demonstrated that improvements in HF care could contribute to key LTP goals including shorter waits for planned care and reduced pressure on emergency hospital services.2
Of the sample of patients who died within seven days of non-elective HF admission in the UK in 2016, 78% had known HF, with 45% under hospital and 35% under community HF teams. Of patients known to have HF, 22% were waiting for a procedure at the time of death, including eight of nine patients referred for transcatheter aortic valve implantation (TAVI).
Admission for 30% of patients in the analysis was considered avoidable – the commonest reason being that patients should have received end of life care instead of being admitted.
Dr Anderson pointed out that, despite so many patients having known HF, diagnostic uncertainty during ambulance care meant that iv fluids were given as frequently as diuretics. When patients reached the Emergency Department only 8.5% had BNP testing and 12% were triaged to a cardiology ward, increasing to 34% by the end of the admission. Echo was carried out in 44% of patients. Following admission, there was ongoing diagnostic uncertainly and patients received multiple treatments, including iv fluids in 22%. The report concluded that ‘good clinical care’ was provided in 54% of patients receiving cardiology/HF review, compared to an overall ‘room for improvement’ in 53% of new patients with HF.
Amongst the NCEPOD recommendations for improvement were a serum natriuretic peptide measurement in the first set of blood tests in all patients with acute breathlessness and suspected acute HF and an echo within 48 hours. In addition, better pathways should be in place for patients with advanced HF to access palliative care when appropriate. Dr Anderson suggested that a first step should be to ensure that all patients are assessed by the on-call cardiology specialist registrar.
Ensuring patients receive the right care, at the right time, from the right team in the right place is the key to developing an effective HF care pathway, Cheltenham GP and GPwSI in Cardiology, Dr Jim Moore told delegates. Although there are few treatment changes in the latest NICE guidance,3 there are many recommendations about the roles of healthcare professionals – with emphasis on good communication.
“Sitting on the NICE committee and hearing from the patient representative was very illuminating because again and again we heard about miscommunication – between primary care and secondary care, primary care and patients and secondary care and patients. So I hope this has been sufficiently addressed in the guidelines,” said Dr Moore.
He explained that, at the first clinical suspicion of HF based on symptoms (breathlessness, fatigue and fluid retention attributable to cardiac dysfunction), patients should have an NT-proBNP test which, if elevated, should trigger transthoracic echocardiography with a specialist opinion (Figure 1). He added that NT-proBNP is preferable to BNP because its stability enables it to be processed several hours after the blood sample is taken.
“The guidelines stress the importance of urgent NT-proBNP testing. If the level is raised, it’s up to the referral agency to decide whether the patient should be seen within two or six weeks but it’s our responsibility to ensure the test is done urgently in the first place. The prognosis for heart failure is worse than for some forms of cancer so it is clear why urgent testing is so important,” said Dr Moore.
He presented retrospective primary care data on 36,748 patients with HF which showed that 44% with at least one relevant symptom in the previous five years had no natriuretic peptide test, echo or referral,4 suggesting there is considerable room for improvement in guideline implementation.
Dr Moore stressed the importance of close collaboration between primary care clinicians and the core specialist HF multidisciplinary team (MDT). The MDT should make the diagnosis of HF, provide newly diagnosed patients with appropriate information, manage those with New York Heart Association Class III-IV HF, start new medicines and optimise treatment.
“In Gloucestershire Heart Failure Service, the first consultation is 45 minutes and we use every minute of it because we need to give patients a lot of information and discuss treatment. We give them a follow up appointment two weeks later, and we provide a care plan with a single A4 sheet of summary points because this is more likely to be read,” explained Dr Moore.
With full evidence-based treatment, annual HF mortality can be reduced from about 50% to 7%, he said. Yet recent data show that only 35% of patients with HF receive optimised doses of angiotensin converting enzyme inhibitors (ACE-Is) and beta-blockers (BBs).5
Dr Moore commented that although the updated NICE guidance recommends additional mineralocorticoid receptor antagonists (MRAs) only for patients with HF with reduced ejection fraction (HFrEF) on ACE-Is and BBs with continuing symptoms it is now widely accepted that all patients with HFrEF should be considered for triple therapy.
Stabilised patients can return to primary care where they should be reviewed, including renal function assessment, at least every six months.
Dr Moore pointed out that, as many of these patients are likely to be monitored annually for existing vascular disease or diabetes by practice nurses in long term conditions clinics, HF reviews can be carried out at the same time and results recorded in standard templates.
Referring to his own 10,000-patient practice, Dr Moore reported that only 14 out of 112 patients with HFrEF were not seen routinely in a chronic disease clinic.
“My practice nurse who has had heart failure education sees patients with anything up to four comorbidities during a variable length appointment – two comorbidities in 15 minutes, four comorbidities in 30 minutes,” he said.
In conclusion, Dr Moore explained that, although HF will not be part of the new CVDprevent audit included in the new five-year GP NHS contract, HF is expected to be incentivised alongside blood pressure, cholesterol and atrial fibrillation for the new primary care networks. In addition, an annual HF functional review is likely to be included in the next NICE Quality and Outcomes Framework (QOF) indicators.
Creating the right environment for service change and monitoring the outcomes of implementation are two key elements for effective delivery, and solutions need to be developed by MDTs – not for them, pointed out Dr Simon Woldman, Consultant Cardiologist and Director of Barts Heart Centre, London.
“We need to think radically and differently about how we deliver heart failure services in order to improve them, but that is threatening. So we need to get buy-in by creating a sense of urgency and then encourage local teams to think about the changes that are needed and how to implement them,” he said.
Dr Woldman showed how University College London HF specialists established their aims, methods, pathways and tools for improving services (Figure 2), and he underlined the importance of ensuring the right roles for the right specialists, eg. consultants initiating treatment plans and identifying patients for advanced imaging and therapies and community HF nurses for completing uptitration, continuing patient education and as a rapid point of contact.
Monthly audit of guideline-recommended elements of HF care can have a major impact on successful implementation. Investigating reasons for HF readmissions within 30 days can indicate areas for improvement, and comparisons with neighbouring areas can provide useful insights.
Dr Woldman differentiated between process measures and outcome measures, pointing out that process measures give information about the quality of the provider – whether they are following HF guidance and treating patients. However, it is outcome measures, such as mortality, quality of life, patient-reported outcome measures (PROMS) and the harder to monitor patient-reported experience measures (PREMS) that are more patient oriented.
Interpreting data requires care. For example, HF prevalence may be well below the 1% average in areas with a young population but a low prevalence reported in an area with an ageing population may be indicative of low NT-proBNP testing.6 A high prevalence accompanied by a low HF admission rate suggests that patients are being adequately treated.
“We must wean ourselves off dependence on process data and start looking at whole system measurements – difficult though that can be. Preventing readmissions is just as much about organisation as about therapy and easily available data can be used to build the case for services,” concluded Dr Woldman.
“How long does a typical secondary care physician listen to a patient tell their story before interrupting?” asked Professor Martin Cowie, Professor of Cardiology, Imperial College London, during his introduction to a series of presentations about getting the patient experience right. The evidence suggests just 17 seconds.
Professor Cowie urged clinicians to start their consultations with a ‘tell me all about it’ open question to enable patients to talk about their past, their present, their issues and what is important to them.
He discussed the results of a meta analysis of 25 qualitative studies of patients living with chronic HF which showed that the time around diagnosis has a particular impact and the day-to-day uncertainty greatly influences emotional well-being, including a sense of loneliness.6 External resources helped the patient and their family whose typical aim was to live with the condition and adapt and cope.
The latest NICE guidance highlights the importance of providing information whenever needed – discussing prognosis sensitively, openly and honestly including the uncertainty of HF, and revisiting the discussion as the condition evolves.
Professor Cowie also drew attention to NCEPOD recommendations for including the patient and family in decisions about therapy escalation (Figure 3). For those with advanced disease, pre-emptive discussions in clinic or primary care are recommended about treatments that would not be beneficial, together with opportunities for palliative care to prevent unnecessary admission.
“As we think about all of our services and what we need to do differently, we need to understand the processes and how they drive outcomes but we also need to think about how patients feel as they go through our services and what their experience is like. It’s an aspect we’ve probably neglected in the past and that needs to change,” said Professor Cowie.
Advanced Communication Skills can help to improve patient and carer outcomes and experience of HF care in many situations, not just when breaking bad news and discussing prognosis, Louise Clayton, Advanced Nurse Practitioner at University Hospitals of Leicester told delegates. She recommended two-day, small group training prgrammes for enabling HCPs to practise and improve their skills in a safe environment.
“All our conversations impact on outcomes whether we’re talking about medication adherence, patient/healthcare professional relationships, planning care or shared decision making and, all too often, there are missed opportunities for advanced communication skills,” Ms Clayton pointed out.
She explained that active listening and sharing, rather than imparting, information leads to a collaborative partnership for helping patients talk about difficult subjects that come up regularly, such as diagnosis, prognosis, invasive procedures, DNAR and down titration of therapy.
Evidence suggests that patients with advanced HF want information about prognosis and what to expect from living with their condition – discussed at a time when they can process the information and feel in control.
“People want to have these conversations before they become acutely ill or are in hospital and they want discussions to help plan their care, especially when family members are care providers, so they do not feel they are becoming a burden,” said Ms Clayton.
Caregivers of patients with HF also need to be included; research suggests that carers feel they are on a ‘physical and emotional rollercoaster’ and they report poor communication, living with uncertainty, and lack of service provision as key challenges.7
Ms Clayton explained that potential barriers to communication can be patient and disease related, professional related or system related,8 and she described a number of approaches to facilitate conversations with patients and carers (Figure 4).9
Ms Clayton concluded that, whenever possible, HCPs should plan ahead so there is plenty of time for difficult consultations to be held in the right environment, and ensure continuity of discussion.
Working alongside cardiology, palliative care has much to offer in improving quality of life – and sometimes prognosis – for patients and carers, and both specialties have much to learn from each other (Figure 5).
“From diagnosis onwards, we have a range of services for patients with heart failure but most of our referrals come too late, often in the last year of life. We can do so much more if we can establish relationships earlier on – our work is about quality of life, not just quality of death,” said Dr Sharon Chadwick, Medical Director and Consultant in Palliative Care at the Hospice of St Francis, Berkhamsted, Hertfordshire.
She explained that palliative care for HF encompasses physical symptoms related to all comorbidities, psychological concerns and social, spiritual and existential issues. It ranges from supporting the use of subcutaneous furosemide, when appropriate, to de-prescribing, advance care planning, considering the needs of carers and bereavement support.
Control of physical symptoms of HF may include management of anaemia, electrolyte disturbance, renal impairment, poor diet or appetite problems. Opioids may be considered for breathlessness with or without pain, while taking into account the potential for constipation. Depression and anxiety are common psychological symptoms in HF and treatment may include cognitive behavioural therapy (CBT) as well as drugs. Patients often need help in coming to terms with loss of function and finding ways to replace what they have lost but much can be done to reduce the so-called ‘Calman Gap’ between hopes and aspirations and reality by modifying expectations and improving symptom control.
Dr Chadwick pointed that de-prescribing can not only reduce side effects, it often leads to improved renal function. It can also have implications for symptomatic postural hypotension and risk of falls and bleeds in patients on anti-coagulation.
Advance care planning facilitates discussions about whether further hospital admissions are appropriate (and their alternatives), making wills and deciding about preferred place of death.
Cardiac resynchronisation therapy defibrillators (CRT-Ds), which are being used in a growing number of patients, can raise particular challenges because they are a continuing physical and psychological reminder of HF. As patients near the end of their life it may not be easy to talk about switching off the defibrillator component but it can avoid distressing situations for dying patients. If a patient has a DNACPR decision it is important to record that they have an active defibrillator on the form and discuss this with patients and caregivers.
Dr Chadwick concluded that, ideally, one member of a palliative care team should have a special interest in HF but, unfortunately, commissioners frequently don’t recognise this need.
“We can’t look after every patient with heart failure but we can dip in and out at all stages of their disease, and we can support our colleagues across the heart failure community, particularly with the most complex cases,” she said.
Exercise-based rehabilitation improves health-related quality of life for patients with HF and reduces their risk of unplanned hospitalisation, yet fewer that one in 10 patients in the UK currently receive it. A more modern approach is therefore needed to extend delivery, advised Professor Rod Taylor, Chair of Population Research at the Institute of Health and Well Being at the University of Glasgow and Chair of Health Services Research at the University of Leeds.
“We really do need to be innovative and modern and think of alternative methods of delivery to traditional outpatient programmes and consider home/community and digitally based systems. We also need to take account of the comorbidities that many of these patients have and understand that we’re not just treating their heart, we’re treating the person,” he said.
Data from the 2019 Cochrane Review of exercise based cardiac rehabilitation for HF showed that, although the intervention did not reduce all cause mortality, it did reduce hospitalisations by 30%, largely driven by a reduction in HF-related admissions by 41% (Figure 6).10 There was also a statistically significant and clinically meaningful improvement in quality of life as measured by the Minnesota Living with HF questionnaire (MLHFQ) score. A subsequent analysis showed consistent benefits of exercise-based cardiac rehabilitation on quality of life in HF, irrespective of age, gender, NYHA class and other factors.11
“Everybody with HF should benefit from cardiac rehabilitation and this is what NICE recommends,” said Professor Taylor. “In patients with heart failure with preserved ejection fraction, we have evidence of improved mechanistic outcomes though we are still waiting for evidence of benefits for quality of life and events.”
The LTP’s goal is for 85% of patients to receive cardiac rehabilitation by 2028, and NICE recommends that exercise based cardiac rehabilitation should be offered in a format and setting that is easily accessible. A Cochrane review of home-based and centre-based cardiac rehabilitation showed they were equally effective in improving exercise capacity, blood pressure, cholesterol and other factors.12 However, most of the studies were in patients with coronary artery disease rather than HF.
The REACH-HF (Rehabilitation EnAblement in CHronicHeart Failure) study showed that a facilitated self-care and home-based cardiac rehabilitation programme provided a significant and clinically meaningful improvement in MLHFQ score compared to usual care (p=0.025).13 At a cost of about £450 per patient for training and manuals etc, REACH-HF has a cost per quality adjusted life year (QALY) of £172014 – well below the £20,000 threshold for cost effectiveness used by NICE.
REACH-HF was launched at four Beacon sites in England (Belfast, Gloucester, Wirral and London) in Summer 2019, and in three Health Boards in Scotland. The REACH-HF manual is being digitised for App and internet use and steps are being taken to simplify training and make it as accessible as possible.
“We are embedding REACH-HF in real world practice and linking it to routine data to see if we get the same results as in the clinical trial. One size probably doesn’t fit all and we may need a hybrid model whereby patients may initially have centre-based rehabilitation and then be discharged to a home setting,” concluded Professor Taylor.
Recent HF drug trials have provided valuable insights into optimal dosing, anticoagulation, neurohormonal blockade in HFrEF and HFpEF and the role of novel anti-diabetic therapies. Dr Klaus Witte, Senior Lecturer and Consultant Cardiologist at the University of Leeds, brought delegates up to date with the implications of recent trial results for routine patient care.
“Heart failure is not ‘done’. Even patients with mild symptoms who are on triple therapy have a three-year mortality of 25% so we need to learn how to optimise medical therapy in a way that will not only extend life but also make people feel better,” he said.
Dr Witte presented data from studies showing the importance of dose titration of BBs and ACE-Is.15 In patients with chronic heart failure, followed up for four years, those with diabetes had a higher mortality despite similar doses of BBs and ACE-Is to those without diabetes. Increasing BB dose was associated with lower mortality in both groups, with greatest benefit in patients with diabetes.
Using comparative data from patients with/without optimised bisoprolol dosing, Dr Witte showed that mortality was significantly higher in those who failed to achieve a dose of at least 5mg and many of these patients did not have contraindications (low heart rate or blood pressure) for treatment.
“When patients look at us in dismay at the suggestion of a dose increase, we must help them understand that the higher the dose, the better – it’s not just about getting on the tablet, it’s about getting on the highest possible dose,” Dr Witte explained.
Turning to anticoagulation in high risk patients, Dr Witte discussed recent studies aimed at achieving the mortality advantages seen with warfarin, but without the bleeding risk. The placebo controlled Commander-HF study of rivaroxaban 2.5mg bd in patients with HFrEF in sinus rhythm with a recent hospitalisation for decompensation, and underlying coronary artery disease, failed to achieve its primary composite endpoint of reduced death, MI or stroke.16 However, the COMPASS study in patients with stable coronary artery disease demonstrated a survival advantage (CV death, stroke or MI) with rivaroxaban 2.5mg bd + aspirin 100mg od compared to aspirin alone, though with more major bleeding events, with patients with a history of HF showing particular benefit.17
“We need further analyses of the heart failure sub group in both of these studies, though we do already know that the heart failure sub group in COMPASS did benefit,” said Dr Witte.
The evidence for enhanced neurohormonal blockade in patients with HFrEF is clearer, and recent studies have extended understanding of how this approach should fit into clinical practice. Following the PARADIGM-HF study showing that sacubitril/valsartan reduced mortality and HF hospitalisation compared with enalapril in patients with symptomatic HF,18,19 together with sudden death and death due to worsening HF,20 the PIONEER-HF and TRANSITION studies have provided additional information about the role of sacubitril/valsartan.
In the PIONEER-HF study of patients stabilised during hospitalisation with acute decompensated HF, sacubitril/valsartan resulted in a 29% greater reduction in the primary endpoint of NT-proBNP from baseline than enalapril. This was accompanied by improvements in exploratory clinical endpoints, including rehospitalisation to week 8 (8.5% vs 13.6%, respectively p=0.021).21
“This suggests we may want to revisit our paradigm of uptitrating patients on enalapril for six weeks and then converting them to sacubitril/valsartan,” said Dr Witte.
In the TRANSITION study, approximately half of patients hospitalised with acute HF achieved target dose of sacubitril/valsartan at 10 weeks, irrespective of whether they were randomised to pre-discharge or post-discharge treatment initiation (Figure 7).22 Inpatient initiation did not interfere with concomitant initiation of other HF therapies but was associated with more rapid reduction in NT pro-BNP.23
Unfortunately, the news is less good for HFpEF, with recently presented results of the PARAGON trial in patients with NYHA Class II-IV symptoms and an ejection fraction (EF) ≥ 45% which failed to show a significant benefit of sacubitril/valsartan over valsartan in mortality or hospitalisation endpoints.24
“Pre-specified sub-group analysis of PARAGON showed that if you have mild LV systolic dysfunction you probably do benefit from sacubitril/valsartan, but if you have no evidence of muscle damage and an ejection fraction in the mid 50s or above you probably do not benefit from aggressive neurohormonal blockade and we’re dealing with an entirely different disease process which is not addressed by our current drugs,” said Dr Witte.
Finally, Dr Witte reviewed data from the placebo-controlled DAPA-HF study showing that the SGLT2 inhibitor, dapaglifozin, reduced a composite of worsening HF or CV death in patients with NYHA Class II-IV HF and EF ≤ 40% (16.3% vs 21.2% respectively, hazard ratio, 0.74; 95% CI 0.65 to 0.85, p<0.001).25 Benefits were seen across patient sub groups including those with or without diabetes, and with or without sacubitril/valsartan treatment.
“The patients in DAPA-HF were already on really good treatment so the results lead to a real change in our thinking about heart failure. Dapaglifozin treatment didn’t just reduce heart failure events, it reduced cardiovascular death and there was little heterogeneity of effect across the various sub groups,” concluded Dr Witte.
Though not new, cardiac resynchronisation therapy (CRT) remains the greatest advance in device therapy for HF, said Dr Peter Cowburn, Consultant Cardiologist at University Hospital Southampton. Recent experience with CardioMEMS, an implantable pulmonary artery pressure monitoring system, is encouraging in both HFrEF and HFpEF, he added, and Mitraclip, a novel intervention to reduce mitral regurgitation percutaneously, has shown benefits in some patients with HF and disproportionate mitral regurgitation.
CRT can be delivered with pacing alone (CRT-P) or combined with a defibrillator (CRT-D) for further protection against sudden cardiac death. Dr Cowburn explained that successful CRT depends on patient selection, optimal lead placement, device programming and medical therapy, with patients with broader QRS and left bundle branch block likely to do best. Both types of device have been shown to reduce the combined risk of all cause death or first hospitalisation, with CRT-D significantly reducing mortality by 36% (p=0.003) compared to a 24% reduction (p=0.059) with CRT-P.26 In a subsequent study in patients with NYHA III and a mean QRS of 160ms, CRT-P also reduced mortality by 36%.27
Implantable cardioverter defibrillators (ICDs) also work as a pacemaker and have been shown to reduce sudden death. The newer subcutaneous devices avoid the need for leads within the heart though, as Dr Cowburn pointed out, they do not currently have a pacing back-up function and there is a higher risk of inappropriate shocks.
“ICDs are not for everyone and the patients we see – older patients with multiple comorbidities – tend to do less well than the younger patients who were in the clinical trials,” he said. “However, younger male patients with ischaemic heart disease who have a scar from a previous heart attack are more arrhythmogenic and are more likely to do better with an ICD.”
Dr Cowburn presented results of a recent study of patients with class II/III HF and left ventricular EF ≤35% who received an ICD or medical treatment according to physician’s choice.28 At a median 37.9 months, there was no difference in HF mortality risk between those who did and did not receive an ICD. However, in a separate study of patients with non-ischaemic cardiomyopathy, the presence of scar on MRI was independently associated with reduced mortality (HR=0.45, 95% CI: 0.26-0.77, P=0.003).
“Many people back off using diuretics and ACE inhibitors because of impaired renal function and concerns that patients are ‘dry’. But CardioMEMS enables you to see that pressures are high and you can do more to reduce congestion. You can see each patient as an individual and treat them accordingly,” he said.
Dr Cowburn presented the Southampton experience of CardioMEMS in 28 patients, 22 of whom had more than six months follow up (Figure 8). After implantation, patients needed fewer interactions with HF services, and there was a 69% reduction in all cause hospitalisation and an 85% reduction in HF hospitalisation. The only increase was in consultant clinic reviews.Concluding his presentation, Dr Cowburn briefly reviewed the conflicting results seen with the Mitraclip device. The French MITRA-FR study in patients with chronic HF and severe secondary mitral-valve regurgitation failed to show any benefit in terms of death or hospitalisation,31 but the US COAPT study showed a 47% reduction in hospitalisation and a 38% reduction in death.32
“Patients in the US study had slightly better ejection fraction, slightly smaller hearts and slightly more severe mitral regurgitation but there was a lot of overlap with the French study, and it’s difficult to explain the strikingly different results,” said Dr Cowburn.
With novel treatments for amyloid heart disease soon to be made available, Dr Carol Whelan, Consultant Cardiologist at the Royal Free London NHS Foundation Trust, urged delegates to become familiar with the key ‘red flags’ for this under-diagnosed condition. She explained that identifying the amyloid type is essential for guiding treatment and determining prognosis and anyone seeing a patient with peripheral neuropathy and HF should ‘think amyloid’.
“It’s an exciting time in the world of amyloidosis. Two treatments – patisiran and inotersen – have been approved by NICE for use in patients with neuropathy associated with hereditary transthyretin amyloidosis, many of whom have cardiomyopathy. Tafamidis is going through the NICE process, and new trials of other agents are ongoing,” said Dr Whelan.
Systemic amyloidosis is a multisystem disease caused by deposition of misfolded amyloid protein in tissues and organs. Transthyretin amyloid cardiomyopathy can be inherited as an autosomal dominant trait caused by transthyretin gene (TTR) mutations or by deposition of wild type transthyretin protein (ATTR wt). It occurs mainly in men and, in a post-mortem series, 25% of those over 80 years had cardiac TTR amyloid deposition. Approximately 40-50% of patients with ATTR wt are known to have previous carpal tunnel syndrome, with 50% having atrial fibrillation at presentation.
Dr Whelan explained that cardiac amyloidosis presents as a restrictive cardiomyopathy with progressive diastolic and subsequently systolic biventricular dysfunction and arrhythmia, and diagnosis is frequently delayed. In patients with HF, syncope or bradyarrhythmia and an echo and/or cardiac resonance imaging (CRI) suggestive of cardiac amyloid, scintigraphy with a DPD scan (perhaps followed by histological diagnosis if appropriate) can confirm the diagnosis. Prognosis is currently poor, with a median survival of two to six years, though novel agents acting on different mechanisms show considerable promise.
In the placebo-controlled APOLLO trial of the RNA interference therapeutic, patisiran, which reduces TTR production in the liver, lowered serum TTR and improved neuropathy in patients with hereditary TTR amyloidosis with polyneuropathy.33
Similar findings were reported in the NEURO-TTR study of inotersen, the antisense oligonucleotides which also interferes with TTR production.34
Dr Whelan explained that inotersen has the advantage of subcutaneous administration, rather than infusion needed with patisiran, but requires fortnightly blood tests owing to the risk of thrombocytopenia.
In the ATTR-ACT study in patients with hereditary and wild type TTR amyloid cardiomyopathy, the TTR stabilising agent, tafamidis, was associated with lower all-cause mortality and CV hospitalisation than placebo (p<0.001).35 Over 30 months, all cause mortality was 29.5% vs 42.9% respectively (HR 0.70, 95% CI 0.51-0.96) and CV-related hospitalisation relative risk ratio was 0.68 (0.48 per year vs 0.70 per year, 95% CI 0.56-0.81).
“The survival and hospitalisation benefits were greatest in patients with milder disease, so we need to diagnose patients with cardiac amyloidosis as early as possible,” said Dr Whelan.
A second TRR stabilising agent, AG10, is also in clinical trials.
“For optimal results, we may need a combination of drugs that together reduce TTR production in the liver and stabilise any TTR that is produced. What we are seeing is that, for the first time, there is hope for the heart in patients with amyloidosis,” she concluded.
The NHS Long Term Plan, 2018. https://www.england.nhs.uk/long-term-plan/
National Confidential Enquiry into Patient Outcome and Death (NCEPOD). Failure to function: A review of the care received by patients who died in hospital following an admission with acute heart failure, 2018
National Institute for Health and Care Excellence. Chronic heart failure in adults: diagnosis and treatment. NG106, September 2018. https://www.nice.org.uk/guidance/ng106
Bottle A, Kim D, Aylin P et al. Routes to diagnosis of heart failure: observational study using linked data in England. Heart. 2018 Apr;104(7):600-605.
Conrad N, Judge A, Canoy D et al. Diagnostic tests, drug prescriptions, and follow-up patterns after incident heart failure: A cohort study of 93,000 UK patients. PLoS Med. 2019 May 21;16(5):e1002805.
Woldman S, Riley J. Improving heart failure services for people in London. London cardiac Networks. 2017 http://www.londonscn.nhs.uk/publication/improving-heart-failure-services-for-people-in-london
Fitzsimons D, Doherty LC, Murphy M et al. Inadequate communication exacerbates the support needs of current and bereaved caregivers in advanced heart failure and impedes shared decision-making. J Cardiovasc Nurs. 2019 Jan/Feb;34(1):11-19.
Lawrie I, Kite S. Chapter 7. Communication in heart failure. Heart failure and palliative care: a team approach, 2016.
Parry R, Land V, Seymour J. How to communicate with patients about future illness progression and end of life: a systematic review. BMJ Support Palliat Care. 2014; 4: 331 – 341.
Long L, Mordi IR, Bridges C et al. Exercise-based cardiac rehabilitation for adults with heart failure. Cochrane Database Syst Rev. 2019 Jan 29;1:CD003331. doi: 10.1002/14651858.CD003331.pub5.
Taylor RS, Walker S, Smart NA et al; ExTraMATCH II Collaboration. Impact of exercise rehabilitation on exercise capacity and quality-of-life in heart failure: individual participant meta-analysis. J Am Coll Cardiol. 2019 Apr 2;73(12):1430-1443.
Buckingham SA, Taylor RS, Jolly K et al. Home-based versus centre-based cardiac rehabilitation: abridged Cochrane systematic review and meta-analysis. Open Heart. 2016 Sep 14;3(2):e000463. eCollection 2016.
Dalal HM, Taylor RS, Jolly K et al. The effects and costs of home-based rehabilitation for heart failure with reduced ejection fraction: The REACH-HF multicentre randomized controlled trial. Eur J Prev Cardiol. 2019 Feb;26(3):262-272.
Taylor RS, Sadkerl S, Dalal HM et al. The cost effectiveness of REACH-HF and home-based cardiac rehabilitation compared with the usual medical care for heart failure with reduced ejection fraction: A decision model-based analysis. Eur J Prev Cardiol. 2019 Aug;26(12):1252-1261.
Witte KK, Drozd M, Walker AMN et al. Mortality reduction associated with ß-adrenoceptor inhibition in chronic heart failure is greater in patients with diabetes. Diabetes Care 2018 Jan;41(1):136-142.
Zannad F, Anker SD, Byra WM et al; COMMANDER HF Investigators. Rivaroxaban in patients with heart failure, sinus rhythm, and coronary disease. N Engl J Med. 2018 Oct 4;379(14):1332-1342.
Eikelboom JW, Connolly SJ, Bosch J et al; COMPASS Investigators. Rivaroxaban with or without aspirin in stable cardiovascular disease. N Engl J Med. 2017 Oct 5;377(14):1319-1330.
McMurray JJ, Packer M, Desai AS et al; PARADIGM-HF Investigators and Committees. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014 Sep 11;371(11):993-1004.
Morrow DA, Velazquez EJ, DeVore AD et al. Clinical Outcomes in Patients With Acute Decompensated Heart Failure Randomly Assigned to Sacubitril/Valsartan or Enalapril in the PIONEER-HF Trial. Circulation. 2019 May 7;139(19):2285-2288.
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