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Heart failure (HF) is becoming more prevalent in the setting of significant medical advances. In Ireland alone, 100,000 people are affected, resulting in 20,000 admissions a year. The increased prevalence is in part due to our success in altering the progression of cardiovascular disease. Patients are now surviving heart attacks, cardiomyopathies, hypertensive crisis, cancer, etc, resulting in a larger pool of survivors who then progress to HF. Among adults aged >40, it is estimated that one-in-five will be diagnosed with HF in their lifetime.
Primary care physicians are detecting at-risk patients in their 40s and 50s and altering disease progression. Checking for hypertension, diabetes, dyslipidaemia, advising regarding smoking, obesity, etc, and assessing family history allows GPs to target those at risk. Although enquiring about family history of premature atherosclerosis is the simplest ‘genetic test’ available, it has lost its sensitivity over the decades as people have smaller families, so there are more ‘false negative’ responses.
Despite earlier diagnosis and intervention, as people age, cardiovascular disease will catch up and ischaemic, valvular or hypertensive heart disease will eventually predispose them to HF. Earlier cancer diagnosis and treatments prolong survival, but some survivors will develop HF. Consider HF as an ‘elite club’ where you are already a provisional member, but the timing of your formal entry is yet to be determined. Our target in preventing HF is to ensure entry is as late as possible.
With more HF patients, we will need more HF practitioners. This may be any practitioner with an interest in and knowledge of HF management, whether that be a GP, physician, cardiologist, nurse practitioner, etc. However, they need access to appropriate resources, eg, echocardiography, biomarker and cardiac MRI imaging. They need to identify when a patient is ‘not behaving or not-responding’ as expected and have access to a HF service. The HF specialist may offer further management strategies, including device therapy, new drugs, inotropes or simply advise that the failing heart cannot be improved and have a frank discussion regarding palliative options and support.
An echocardiogram is essential to diagnose heart failure with reduced ejection fraction (HFrEF), which refers to patients with left ventricular ejection fraction (LVEF) <40 per cent, particularly as the European Society of Cardiology (ESC) now divides patients in to those with mid-range LVEF, ie, 40-to-49 per cent, and those with preserved LVEF, ie, those with LVEF >50 per cent. Unfortunately, access to echocardiograms remains limited in Ireland, which delays timely and accurate diagnosis, preventing early treatment that may avoid HF hospitalisations.
Back to basics: Brief recap on the physiology of chronic HF
The normal resting heart ejects 60 per cent of its volume, ie, an LVEF of 60 per cent. If a failing heart has an LVEF of 40 per cent, then there is 60 per cent volume left behind, causing higher pressures and high left ventricular end-diastolic pressure (LVEDP). Blood then backs-up in the pulmonary veins and lungs, causing breathlessness. Over time, the LV volume and stretch result in cardiac dilatation and remodelling, further weakening the systolic function.
The Sabre-Toothed Tiger
The heart in 2017 responds to low LVEF, as it did in Stone Age times. A tiger bites a caveman’s leg, he loses blood, ties a tourniquet, his blood pressure drops and this triggers his primeval responses. Adrenaline release causes increased heart rate and cardiac output. To reduce blood loss, there is vasoconstriction via the renin-angiotensin-aldosterone-sympathetic (RAAS) system.
Fluid retention by renin and aldosterone prevents diuresis, so if the caveman’s family find him, he may survive to hunt another day. This same response is triggered in 2017 in HF when the LV fails with low LVEF but no volume loss. Initially, this may be helpful but in the chronic setting, it is harmful and becomes part of the problem. The low LVEF activates the RAAS system, which starts a vicious circle where adrenaline increases the heart rate and cardiac demand and continued adrenaline activation become harmful. Persistent activation of B1 receptors becomes damaging and is analogous to ‘flogging a tired horse’, where more whipping does not improve the horse’s performance. So how does the heart protect itself?
Intrinsic response: the failing heart protects itself by altering the quantity and ratio of its β receptors. The normal heart has 80 per cent β1 and 20 per cent β2 receptors but the failing heart has 60 per cent β1 and 40 per cent β2 receptors, which ameliorates the response to adrenaline. The failing heart also uncouples the β1 receptors from their energy source, eg, cGMP, resulting in reduced cardiomyocyte contraction.
Extrinsic support: Treatment with ‘trial-proven’ beta-blockers, eg, carvedilol, metoprolol succinate, nebivolol and bisoprolol, improves morbidity and mortality in chronic HF by 35 per cent. Only carvedilol in the COPERNICUS trial showed benefit in severe HF patients, New York Heart Association (NYHA) class IIIb/IV. Carvedilol is a non-selective beta blocker with β1-, β2- and α-blocking effects. The α blockade causes vasodilation, allowing the failing heart to offload at the same time as its β receptors are being blocked. It is important to recall that the BEST trial in chronic HF with bucindolol showed no benefit, so not all beta-blockers are equal. Even HF beta-blockers can cause harm if not used appropriately, eg, in high doses to a failing heart, they cause hypotension, acute renal failure and possibly death.
Debate on whether beta-blockers exert their benefit by simply slowing the heart rate or by other mechanisms continues. Ivabradine slows the heart rate by inhibiting the I(f) channel of the sinoatrial node. Although it didn’t improve the primary end-point in the SHIFT study, it did reduce HF hospitalisation. Ivabradine is useful for patients with persistent rates >70bpm but especially for those who are beta blocker-intolerant, eg, asthmatics.
Exogenous stimulation of β receptors with inotropes such as dobutamine or by calcium sensitisers such as levosimendan increases morbidity and mortality, but are useful in acute decompensated HF when used cautiously by experienced physicians and in the palliative situation.
Intrinsic response: When the LV is stretched by extra volume, the endocardium releases natriuretic peptides like BNP, which excretes both salt and water. A high BNP indicates the heart is defending itself in response to LV stretch. Other peptides such as adrenomedullin and bradykinin have advantageous properties on vessels and renal perfusion in the HF setting. These are the body’s counter-regulatory response to persistent RAAS stimulation.
Extrinsic support: Treatment with an angiotensin receptor blocker and neprilysin inhibitor (ARNI) has been shown in the PARADIGM-HF study, published in August 2014, to reduce death from cardiovascular cause or HF hospitalisation by 20 per cent, reduce death from cardiovascular cause by 20 per cent, reduce HF hospitalisation by 21 per cent and all-cause mortality by 16 per cent. This was the first overwhelmingly positive HF drug study since the beta-blockers trials of the 1990s.
The PARADIGM-HF trial compared LCZ696, a combination of valsartan (ARB) and sacubitril (neprilysin inhibitor) compared to enalapril (ACEi) in stable HF patients on optimal treatment with persistently low LVEF <40 per cent. Sacubitril blocks the breakdown of BNP and other peptides and therefore ‘enhances’ the body’s own defence mechanism. LCZ696 is marketed as Entresto in Ireland.
Most patients in PARADIGM-HF were NYHA class II (72 per cent) or III (22 per cent). Although described as a ‘stable HF population’, they still carried significant risk, eg, mean LVEF 29 per cent, BNP 255pg/mL and 36 per cent had AF. The high primary end-point rate of 26.5 per cent on enalapril vs 21.8 per cent on LCZ696 suggests they were not low risk, even if stable. LCZ696 showed a significant benefit across all subgroups and improved quality of life, as demonstrated by KCCQ. LCZ696 is substituted for an ARB or ACEi but it is important that the ACEi is stopped >36 hours before initiation to avoid angio-oedema.
Patients in the LCZ696 arm were on less diuretic, as investigators were encouraged to reduce drugs to allow up-titration. Perhaps enhancing the endogenous natriuretic response rather than giving loop diuretics was beneficial. There has been the concern that persistent loop diuretic use, may encourage ongoing RAAS stimulation and therefore be deleterious in the long term.
The PARADIGM-HF findings were consistent with previous neutral endopeptidase (NEP) inhibitor trials such as OVERTURE, which compared an ACEi-NEP combination drug omapatrilat vs an ACEi alone, namely enalapril. OVERTURE showed a non-significant 6 per cent reduction in the primary end-point but a significant 9 per cent reduction in CV death or hospitalisation. Patients on omapatrilat had a 0.8 per cent risk of angio-oedema, so the drug was not licenced. Omapatrilat caused more hypotension and dizziness without benefit, so there was a concern that we had reached a ‘vasodilatory ceiling’. PARADIGM-HF has reassured us in this regard.
Extrinsic support: The ASCEND-HF trial assessed if boosting the patient’s own BNP response with exogenous BNP, namely an infusion of recombinant BNP called nesiritide in ADHF, was helpful but it showed no benefit over standard care with diuretics. However, this trial looked at the acute decompensation (ADHF) setting.
Intrinsic response: Renin is released due to low renal perfusion and low sodium levels. Renin breaks down angiotensinogen to angiotensin I, which is cleaved in the lungs by angiotensin-converting enzyme (ACE) to angiotensin II; a most potent vasoconstrictor. Angiotensin II acts on the adrenals, causing aldosterone release, which causes salt and water retention at the expense of potassium loss. This results in fluid retention, high afterload and low potassium, all of which exacerbate heart failure. The only agents countering this process are the natriuretic peptides.
Extrinsic support: Treatment with the direct renin inhibitor (DRI) aliskiren showed no benefit when added to enalapril in HF patients and caused more hypotension, renal impairment and hyperkalaemia in the ATMOSPHERE study. Aliskiren is now only used for essential hypertension.
Intrinsic response: Symptoms of heart failure such as fatigue may be viewed as the body reducing its own workload to try to slow the heart rate and allow recovery. Historically, heart failure management was complete bed rest post-MI before there were beta-blockers.
Diuretics: Diuretics reduce the LVEDP, which improves coronary perfusion and dyspnoea. However, excess diuresis drops the LVEDP too quickly, with ‘loss of LV stretch’, which the failing heart requires. This causes hypotension and acute renal failure. The failing left ventricle utilises the Frank-Starling effect, ie, the strength of the heart’s systolic contraction is directly proportional to its diastolic expansion. So, diuretics need to be used judiciously.
Intrinsic response: Adrenaline also acts on α-receptors, causing vascular constriction. This initial adaptive response becomes harmful in the chronic situation, with increased afterload. The body only has the natriuretic peptide (NP) system to counteract the RAAS system, so it is overwhelmed unless assisted externally.
Extrinsic support: Vasodilators such as ACEi have the strongest evidence of benefit (SOLVD, CONSENSUS, SAVE, etc) in chronic HF, which supports their first-line use. ARBs work downstream at the receptor site and are used for ACEi-intolerant patients (CHARM-Alternative). Vasodilation by ACEi, ARB, ARNI, nitrates and hydralazine have all shown benefit in heart failure by either antagonising the RAAS system, enhancing the NP system or by directly dilating vessels.
Extrinsic support: To overcome the aldosterone component of RAAS, mineralocorticoid receptor antagonists (MRAs) such as spironolactone and eplerenone prevent salt and water retention. Aldosterone also increases myocardial collagen, interstitial fibrosis and endothelial dysfunction, resulting in increased stiffness, diastolic dysfunction and potential for arrhythmia. The anti-fibrotic properties of MRAs most likely contributed to the results of the RALES and EMPHASIS-HF trials. If patients have a HF hospitalisation or LVEF remains <35 per cent, they should have an MRA, especially if they have other ‘risk markers’ such as persistently-elevated BNP or QRS duration >130ms. Then, when they are stable, which may take some months, if LVEF remains <40 per cent and symptomatic, NYHA class II/III, then they should be considered for LCZ696 instead of their ACEi/ARB.
After any episode of ADHF, once stabilised and the cause clarified (eg, infection, anaemia, non-compliance, excess fluid or salt intake, etc), patients should be reassessed to prevent recurrences. This is especially pertinent now, as LCZ696 reduces HF hospitalisation by 20 per cent in patients who are at risk.
Device therapy: ‘Back of the envelope’ advice is that those with LVEF <35 per cent after three months of optimal pharmacotherapy (OPT) should be considered for an implantable cardiac defibrillator (ICD).
Cardiac resynchronisation therapy (CRT) is beneficial in those with left bundle-branch block with QRS >130ms and LVEF <35 per cent, despite three months of OPT.
Decisions regarding device therapy should be made by HF specialists, with full and frank discussion with patients regarding the risks and benefits and the concept of ‘non-responders’.
However, not all patients who are prescribed ACEi or beta-blockers respond and yet we do not label them as ‘non-responders’, so the concept is somewhat subjective.
‘Make the heart great again’
Reverse LV remodelling is the term used to describe when heart size and function, ie, LVEDD and LVEF, improves and this is usually assessed by echocardiogram or MRI. A dramatic example is Takotsubo cardiomyopathy, where a dilated LV with LVEF 25 per cent may be normal size, with an LVEF 60 per cent within weeks. Reverse LV remodelling when accompanied by normalisation of BNP is reassuring. In chronic HF, after initiation with beta-blockers, the time course of reverse LV remodelling is that 60 per cent of the response at one year will be seen by three months (McCaffrey et al). This is an important observation, as it suggests that you should wait three months after significant therapy changes before reviewing LVEF when deciding on management, eg, an ICD, as the LVEF may be >35 per cent.
‘Medicine by numbers’ or ‘tick-box medicine’ is a concern, because doctors assume heart failure patients should be on all proven therapies, eg, ACEi/ARB/ARNI, beta-blockers, MRA, ICD, CRT, diuretic, +/-digoxin, +/- fluid restriction, +/-statins, +/-aspirin, etc, but they shouldn’t. Patients should be on what is appropriate for them at whatever stage they are at during their HF course. Their treatment may be targeted to improve symptoms, to reduce hospitalisation or to prolong life, or perhaps all of the above. Most ‘real-life’ HF patients would not meet the criteria for large phase 3 trials, either due to their young age (<55), comorbidities or the transient nature of their HF.
Therefore, we often use Level of Evidence C (consensus of opinion or small studies or registries) and often Class of Recommendation II (conflicting evidence or divergence of opinion) decisions to guide us. We also use our anecdotal experience, our familiarity with certain HF drugs, our patients’ ability to comply with instructions and our access to diagnostic services and consideration of costs both to the patient and the payer before we suggest various treatments, doses and combinations.
Going forward, the main goal remains HF prevention by reduction of modifiable cardiac risks. ESC HF prevention guidelines now include SGLT2 drugs, like empagliflozin for type 2 diabetics to delay the onset of HF (EMPA-REG OUTCOME trial). Future treatments may include anti-inflammatory therapies.
Recently in the CANTOS study, stable coronary artery disease patients with elevated CRP given canakinumab, a monoclonal interleukin-1 beta antibody, had less major adverse cardiac events (MACE). Previous HF studies, eg, RECOVER, with anti-inflammatory agents like etanercept, a TNF inhibitor, were negative, although investigators believe this was a dosing issue. So the inflammatory component of chronic HF remains a future target. In PARADIGM-HF, there was still a 21.8 per cent primary event rate in the ARNI arm where patients were on OPT in centres of excellence, so more needs to be achieved, as event rates would be still higher in ‘real-life’ practice.
We cannot reduce the ageing process and therefore ‘stiff hearts’ with impaired diastolic function and subsequent preserved systolic heart failure (HFpEF) is inevitable. Therefore, if we live long enough, we will all join the HF club but our goal as physicians is to postpone entry. Fortunately, with the HF therapies available to us, progress is being made and although the improvement is incremental, remember, with every positive adjustment, someone’s life is enhanced.
References on request