European Society of Cardiology Heart Failure Guidelines 2021: What should we be doing in current practice?

Introduction

The 2012 European Society of Cardiology (ESC) Heart Failure (HF) guidelines recommended, in its 61 pages, the use of three different drug classes for the treatment of “systolic” HF while acknowledging “diastolic” HF as a separate and untreatable entity¹. The 2021 ESC-HF guidelines, in its 128 pages, cover a period of scientific study during which the understanding and treatment of HF has advanced more than for any other chronic condition².

HF is increasingly treated by a wide range of clinicians and this editorial attempts to distil the most recent guideline into 5 key “take-home” messages.

“All at once” heart failure treatment

The 2021 guideline marks a significant change in HF management. It advises that once diagnosed, patients with HF and a reduced ejection fraction (HeFREF) should be treated with two renin-

angiotensin-aldosterone-system inhibitors (either an angiotensin converting enzyme inhibitor (ACEI), an angiotensin receptor blocker (ARB), or sacubitril-valsartan; and a mineralocorticoid receptor antagonist (MRA)); a beta-blocker; and a sodium-glucose co-transporter-2 inhibitor (SGLT2I); plus diuretic for those with venous congestion (Table 1).

Treatment with all four drug classes is associated with an extra 3 years of life free from HF hospitalisation or death for an 80 year old, and an extra 8 years for a 55 year old with HeFREF compared to treatment with an ACEI or ARB and beta-blocker alone (3). Each treatment has additive prognostic benefit independent of the others³,3 and the guidelines thus recommend abandoning the notion that drugs such as MRA or ARNI should only be introduced in patients with ongoing symptoms despite treatment with an ACEI or ARB, plus beta-blocker⁴.

While the improvements in prognosis are remarkable and very welcome, it presents several questions such as; in what order and over what time scale should each drug be introduced? Different approaches might include low dose beta-blocker plus SGLT2I followed by sacubitril-valsartan and MRA; an alternative might be low dose sacubitril-vasartan and SGLT2I followed by beta-blocker and MRA (figure 1)^5-7.

While the exact order is likely to be unimportant – and is not discussed in the guideline – those caring for the patient must not lose sight of the ultimate goal of achieving quadruple therapy, despite apparent clinical stability.

Another relevant question is who should take the lead for medicines optimisation? Heart failure specialist nurses are trained for just such a role but their availability is patchy nationally⁸. Primary care specialists have enormously high workloads, and specialist hospital clinics lack capacity⁹. Additionally, the increasing use of remote consultations, which make assessment of clinical status, blood pressure, heart rate and rhythm, and renal function difficult, present another barrier to adequate medicines optimisation.

An additional problem is that a patient recently diagnosed with HeFREF who is tolerant of all four medications is likely to be taking 5-6 tablets per day, not including diuretics or treatments for co-morbidities. Polypharmacy and its consequences, such as non-adherence¹⁰, will be unavoidable for patients with HeFREF.

Heart Failure Phenotype Definitions

The 2016 ESC-HF guidelines introduced the new concept of HF with a mid-range ejection fraction to describe those lying in the grey zone between an obviously normal left ventricular ejection fraction (LVEF) on echocardiography, and an obviously reduced LVEF.

Figure 1. Comparison of ESC-HF 2016 and 2021 recommendations for medical treatment of HeFREF (adapted from Packer and McMurray, 2020; and Straw et al, 2021)^6,7. _{ESC – European Society of Cardiology, HF – Heart Failure, HeFREF – Heart Failure and a Reduced Ejection Fraction}

The 2021 iteration renames this “HF with a mildly reduced ejection fraction (HeMREF)” and gives weak recommendations for medical therapies for patient with an LVEF between 40-50% (Figure 2).

While based on some clinical data^11-17, this is also an attempt to mitigate two concerns with basing treatment decisions on LVEF measured by transthoracic echocardiography:

• dividing a continuous variable (LVEF) into groups based on arbitrary cut-offs will lead to misclassification, which may mean some patients do not receive treatments that may benefit them
• there is much inter- and intra-observer variability when measuring LVEF: a patient who has an LVEF of 42% measured one day by one operator, may have an LVEF of 38% another day¹⁸.
• no trial has actually deliberately set out to investigate patients in this specific subset of patients with heart failure: all studies in patients with heart failure and normal ejection fraction have shown that the benefit of intervention increases with decreasing initial left ventricular ejection fraction

Although not in the 2021 guideline, the recent EMPEROR-Preserved study which showed a

reduction in HF hospitalisations (but not total hospitalisations) amongst patients with an LVEF <50% will almost certainly add SGLT2I to the list of treatments for patients with HeFMREF (Figure 2)¹⁴.

The term to describe patients with the HF syndrome and an LVEF >50% is controversial and, after being put to a vote, the guideline committee adopted the term “HF with a preserved ejection fration” rather than “HF with a normal ejection fraction”, despite being inaccurate. For example: a patient with an LVEF of 70% has a heart attack and later presents with breathlessness and is diagnosed with HF, an echocardiogram finds an LVEF of 55% - the LVEF cannot be described as “preserved”, but it would lie within the normal range.

Changes to Device Recommendations

Primary prevention ICD for patients with non-ischaemic cardiomyopathy

None of the landmark studies that established the prognostic benefit of implantable cardioverter defibrillator (ICD) implantation in patients with HeFREF specifically enrolled patients with non-ischaemic cardiomyopathy^19-22. Those that did were either neutral²³, or were closed early^24,25.

Figure 2. Medical management of HeFREF and HeFMREF (adapted from McDonagh et al, 2021)². _{† - Although the combined endpoint was not statistically significant, there was a significant reduction in CV mortality with βB in patients with HeFMREF vs. placebo; ‡ - The EMPEROR-Preserved data does not feature in the 2021 ESC-HF guideline and is likely to carry a greater recommendation than level C in the next iteration; * - there was a significant reduction in the primary outcome of HF hospitalisation, aborted cardiac arrest, or CV mortality with spironolactone vs. placebo for patients enrolled in the Americas. HeFREF – heart failure and a reduced ejection fraction; HeFMREF – heart failure and a mildly reduced ejection fraction; βB – beta-blocker; SGLT2I – sodium-glucose co-transporter-2 inhibitor; MRA – mineralocorticoid receptor antagonist; ARNI – angiotensin receptor neprilysin inhibitor; ARB – angiotensin receptor blocker; ACEI – angiotensin converting enzyme inhibitor; HR – hazard ratio; CI – confidence interval; HF – heart failure; CV – cardiovascular; IPD – individual patient data.}

The DANISH trial, which recruited only patients with non-ischaemic cardiomyopathy, found no reduction in all-cause mortality with ICD over usual care (although there was a signal that ICD implantation may reduce the risk of all-cause mortality in those aged 68 or younger (16% in the ICD arm vs. 21% in the control arm; HR = 0.64 (95% CI 0.45-0.90; P=0.01)²⁶. Only 70 out of 1116 patients recruited had sudden cardiac death (SCD) over a 5 year follow up period²⁶. Although patients with an ICD were 50% less likely to die suddenly, more patients in the ICD group had inappropriate shocks (N=34; 6%) than had SCD (N=24; 4%)²⁶. Thus, the level of recommendation for primary prevention ICD in patients with HeFREF has been downgraded.

It is worth noting that the trials of primary prevention ICD are nearly twenty years old. In that time the rate of SCD in patients with HeFREF has fallen by 44%²⁷, with reductions in SCD seen with ACEI, beta-blocker, MRA²⁷, ARNI²⁸, and SGLT2I²⁹. ICD implantation has a complication rate between 3-9%³; although it remains a major part of HF treatment, the real prognostic benefit of primary prevention ICDs in the age of quadruple therapy is unknown.

CRT for patients with LBBB and QRS duration 130-149ms

Two individual patient-data meta-analyses from the landmark trials of CRT have suggested the prognostic benefit of CRT was less certain with a QRS duration 130-149ms, with a signal towards potential harm in patients with a QRS <130ms (Table 2)^{31, 32}.

Although the strength of the recommendation has changed between 2016 and 2021, the data on which they are based in the referenced meta-analyses remain the same. This perhaps reflects the dilemma facing all guideline committees: should recommendations be based on the effect seen in sub-groups within a trial; or should they be based on the overall observed effect of treatment? In the case of the former, sub-group analysis may be statistically underpowered. In the case of the latter, some patients who might benefit from the treatment are excluded.

Downgrading the recommendation acknowledges the weaknesses in the evidence bases while accepting that there may be subgroups of patients who lie outside of the study entry criteria who may also benefit from the treatment.

Oral treatment on discharge

Only ~50% of patients with HeFREF admitted to hospital in the UK are discharged on triple therapy³³. The reasons for this are unknown although it is probable that some patients are unable to tolerate multiple drugs that reduce blood pressure after a prolonged period of diuresis. However, the National HF Audit has consistently found that patients discharged from specialist wards are more likely to be prescribed an ACEI, ARB, MRA and beta-blocker than patients discharged from general medical wards (Table 3) and the absence of specialist knowledge or experience may be a factor³³. Registry data also consistently suggests that under-treatment is a common problem in patients with HF and likely to be a result of a degree of clinical inertia³⁴. The 2021 ESC-HF guidelines recommend that all patients admitted with heart failure are prescribed “evidence-based oral treatment” and have their oral medications “optimised” pre-discharge. It is unknown if this is realistic in practice, but it is a logical goal as those who have the most to gain from HF medications are those most at risk. For example, the readmission and mortality rates are 23% and 15% within 1 month of discharge^33,35 and the prognostic benefit of HF medical therapy is seen within 30 days of initiation^36-38. However, “medicines optimisation” in patients with HeFREF is often complicated, and takes many weeks to achieve. It may be more practical to develop and invest in systems that allow optimisation to take place over a series of out-patient visits shortly after discharge.

The National Institute for Health and Clinical Excellence HF guideline (and now also the ESC-HF guideline) recommend that patients are seen in clinic within 2 weeks of discharge following admission with HF; one purpose of this clinic visit is to initiate or up-titrate medications^2,39. However, many HF services do not meet this target³³, and efforts will be further complicated by the barriers to out-patient care as a result of the COVID-19 pandemic. Initiating quadruple therapy before discharge in patients with HeFREF may be the best opportunity to do so, whilst also providing a chance to assess tolerance.

Encouraging self-management

Self-management has been an important part of HF guidelines for years, yet 2021 is the first year to give self-management advice to patients a class I level A recommendation (Figure  4) alongside specific goals of patient education and how this might be achieved (Table 4).

Heart failure is a diagnosis for life and the specialist-patient relationship is long-term; empowering the patient through education and self-management advice at an early stage can help ensure it is, at least at the beginning, a happy one ^a.

Figure 4. Self management advice for patients with heart failure (adapted from McDonagh et al, 2021)². _{† - only seen with ACEI. OTC – over the counter; NSAIDS – non-steroidal anti-inflammatory drugs; ARB – angiotensin receptor blocker; ARNI – angiotensin receptor neprilysin inhibitor; D&V – diarrhoea and vomiting; g – grams; L – litre; kg – kilograms; HF – heart failure}

Conclusions

The 2021 ESC-HF guideline has been delivered ‘with little fanfare’ but deserve recognition for its effort to incorporate recent rapid scientific advances in the field into a logical guideline for clinical practice. While the practicalities of some of the recommendations may require further discussion, for example around quadruple therapy, the rationale is persuasive. Patients with HF, and those that care for them, are being well served.

Disclosures

None

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