Summary and Comparison of the 2022 ACC/AHA/HFSA and 2021 ESC Heart Failure Guidelines

Cardiac magnetic resonance (CMR) imaging is recommended by both guidelines in the assessment of myocardial structure and function in patients where TTE image quality is inadequate. The ESC guidelines recommend CMR for characterization of myocardial tissue in suspected infiltrative disease, Fabry disease, inflammatory disease (e.g., myocarditis), left ventricular (LV) non-compaction, amyloid, sarcoidosis, and haemochromatosis (class of recommendation [CoR]: 1) [4]. The ACC/AHA/HFSA guidelines find that CMR is reasonable in patients with non-ischemic cardiomyopathy if the diagnosis is uncertain based on the recent OUTSMART-HF trial, although with a lower strength of recommendation than the ESC guidelines (CoR: 2a) [6]. ESC recommends that CMR may be useful for assessment of myocardial ischemia in patients with dilated cardiomyopathy who would be suitable for coronary revascularization (CoR: 2b). In comparison, the ACC/AHA/HFSA guidelines recommend the same may be reasonable (CoR:2b).

The ESC and ACC/AHA/HFSA guidelines both suggest non-invasive stress imaging (such as CMR, stress echocardiography, single-photon emission computed tomography [SPECT]) to assess inducible ischemia and viability for patients with coronary artery disease (CAD) who are suitable for coronary revascularization.

For patients with a low to intermediate pre-test probability of CAD or those with inconclusive non-invasive stress tests, computed tomography coronary angiography (CTCA) may be considered to rule out a diagnosis of CAD. Invasive coronary angiography is recommended for patients with persistent angina despite pharmacological therapy and those with an intermediate to high pre-test probability of CAD and heart failure with reduced ejection fraction (HFrEF) who are deemed suitable for coronary revascularization.

Both sets of guidelines align on the recommendation that endomyocardial biopsy should only be performed when a specific diagnosis is sought, and when that diagnosis would significantly impact management, particularly in cases of rapidly progressive HF or worsening ventricular function despite treatment. This approach ensures that the risks of the procedure are justified by the potential impact on guiding the appropriate management decisions.

The ACC/AHA/HFSA guidelines provide detailed recommendations on management for patients at risk for HF (stage A). While not strictly categorized as a stage of HF, the ESC guidelines do also provide a guide to prevention of HF for those with risk factors. Patients at risk of HF (presence of hypertension, diabetes, or vascular disease) should have a screening BNP with intervention if levels are > 50 pg/ml, as it was found to reduce the composite endpoint of asymptomatic LV dysfunction in the STOP-HF trial [11]. Non-pharmacological strategies have been associated with a lower lifetime risk of developing HF. The guidelines suggest regular physical activity of at least 30 min of walking 5 days/week, or 2.5 h/week of moderate intensity exercise in addition to 75 min of vigorous activity per week [12]. Diets such as the Mediterranean, whole grain, plant-based diet, and the DASH (Dietary Approaches to Stop Hypertension) diet [12], as well as diets low in salt (< 1500 mg/day) [12] and a BMI of less than 30 [13] have also been found to reduce progression to symptomatic HF. Hypertension control reduces the risk of developing HF and blood pressure should be targeted at < 130/80 mmHg based on the SPRINT trial, which showed a systolic blood pressure (SBP) goal of < 120 mmHg decreased incident HF by 23% and mortality by 23% compared with an SBP goal of < 140 mmHg [14]. This trial included 9361 participants who were ≥ 50 years old and had hypertension with SBP ≥ 130 mmHg and at least one risk factor for heart disease (age > 75 years old, a Framingham Risk Score for 10-year CV disease risk ≥ 15%, chronic kidney disease, or clinical or subclinical CV disease), and followed them for 5 years to compare the safety and efficacy of intensive lowering of SBP.

The ACC/AHA/HFSA guidelines recommend that patients with type 2 diabetes mellitus (T2DM) and either established CV disease or at high risk of CV disease should be commenced on SGLT2i therapy to improve survival and prevent HF hospitalizations. This recommendation is based on several trials. The CANVAS program compared canagliflozin (n = 5795) to placebo (n = 4347) in patients with T2DM and CV disease or high risk of CV disease [15]. In the primary prevention group, canagliflozin significantly reduced the primary endpoint (incidence of CV death, myocardial infarction (MI), or stroke), HF hospitalizations and progression to albuminuria. Concerns raised in this trial, including increased risk of lower-limb amputations, have not been replicated since, and the black box warning has been removed. The DECLARE-TIMI 58 compared dapagliflozin (n = 8582) to placebo (n = 8578) in patients with T2DM and established CV disease or multiple risk factors. For patients with high CV risk, it was noninferior, but not superior, in reducing major adverse cardiac events, but there was a reduction in blood pressure (BP), HF hospitalizations and improved renal outcomes [16]. The EMPA-REG OUTCOME trial compared empagliflozin (10 mg, n = 2345; 25 mg, n = 2342) to placebo (n = 2333) in patients with T2DM and high risk for CV events and found that empagliflozin resulted in a significant mortality benefit, and was associated with a reduction in HF and all-cause hospitalizations in patients with and without baseline HF [17].

Non-pharmacological management of HF is a focus of the ACC/AHA/HFSA 2022 guidelines with a strong recommendation for regular physical activity and a moderate recommendation for a low-salt diet and cardiac rehabilitation.

Diuretics are recommended in patients with evidence of fluid retention for symptomatic benefit. The four pillars of HF management (RAAS inhibition, beta-blockade, MRA, and SGLT2i) should be initiated in all patients with HFrEF as tolerated. The ACC/AHA/HFSA guidelines suggest initiation and titration of these agents should be individualized based on the patient’s symptoms and signs, function, tolerance, renal function, and comorbidities, however they should be titrated up to the maximum tolerated dose. Optimal benefit comes from initiating all four therapies, rather than sequential maximizing of agents one at a time. The side effects of HF medications are summarized in Table 4.

Inhibition of the RAAS is recommended to reduce morbidity and mortality, with both ACC/AHA/HFSA and ESC guidelines recommending an ARNi as first-line therapy in hospitalized patients with acute HF or following a trial of an ACEi or ARB in outpatients to ensure the patient tolerates RAAS inhibition. If patients are already treated with an ACEi, a 36-h washout period is recommended prior to introducing the ARNi to reduce the risk of angioedema. Evidence for the use of ARNi is growing with the PARADIGM-HF trial finding sacubitril-valsartan reduced the composite endpoint of CV death and HF hospitalisation by 20% when compared to enalapril in patients with symptomatic HF [5]. Biochemically, the PIONEER-HF trial showed that sacubitril-valsartan reduced natriuretic peptide levels when compared to enalapril [20] and structurally, a meta-analysis showed an improvement in LV modelling parameters [21]. ACEi, or ARB if the patient is intolerant to ACEi, are recommended if an ARNi is not tolerated. The key side effects of ACEi are hypotension, hyperkalemia, angioedema, and cough secondary to accumulation of bradykinin and substance P. ARB’s have the same side effects as ACEi, however are less likely to cause angioedema and do not cause due to their mechanism of action. Treatment with beta-blockers reduces the risk of morbidity and mortality in patients with HFrEF, in addition to treatment with an ACEi and diuretic.

Beta-blockers have been shown to improve LVEF, reduce symptoms of HF, and improve prognosis. Patients should be initiated on the lowest dose of beta-blocker when euvolemic and clinically stable, and gradually uptitrated to the maximal tolerated dose. Side effects of beta-blockers include bradycardia, orthostatic hypotension, and bronchospasm. They should be used with caution in patients with asthma [22].

MRAs are recommended in addition to ACEi and beta-blockers to improve symptoms and reduce all-cause mortality, HF hospitalizations, and sudden cardiac death in all patients with HFrEF. Electrolytes need to be closely monitored as patients may develop hyperkalemia, hyponatremia, and/or hypochloremia while taking MRAs. Gynecomastia is more common in spironolactone than eplerenone, due to its antiandrogen effect [23].

SGLT2i therapy is a new addition to the pillars of HF management. The DAPA-HF trial [24] and EMPEROR-Reduced trial [25] are landmark studies that demonstrated benefit of SGLT2i versus placebo. Importantly, survival benefits were seen in patients with and without diabetes. Specifically, the DAPA-HF trial, which enrolled patients with HFrEF (irrespective of diabetes status), found a 26% reduction in the primary endpoint (CV death or hospitalization) in patients receiving dapagliflozin compared to those receiving standard care alone. Similarly, the EMPEROR-Reduced trial, which compared empagliflozin with placebo, found a reduction of 25% in the primary endpoint (CV death or HF hospitalization). Secondary outcomes indicate SGLT2i improve HF symptoms, physical function, and quality of life, and led to fewer hospitalizations and an improvement in all-cause mortality [25]. The diuretic/natriuretic properties of SGLT2i may offer additional benefits in reducing congestion and may allow for a reduction in loop diuretic requirement. Although SGLT2i have been shown to increase risk of genital infections, euglycemic ketoacidosis, and volume depletion due to their additive diuretic effect, they are otherwise well tolerated and should not dissuade clinicians from using this class of medication [1].

In addition to these four drug classes, it is reasonable to commence other medications for HFrEF in certain patient groups. Two key trials, V-HeFT I and A-HeFT, have shown the addition of hydralazine and isosorbide dinitrate to guideline directed medical therapy (GDMT) leads to reduced morbidity and HF hospitalizations, as well as improvement of symptoms in self-identified black patients with HFrEF and NYHA class III-IV [26, 27]. ACC/AHA/HFSA rates this evidence at the highest level (CoR:1), however ESC reports this recommendation as 2a. Ivabradine, an If-channel inhibitor, has reasonable evidence for reducing HF hospitalization and CV death for patients with LVEF ≤ 35% on maximal tolerated GDMT when in sinus rhythm with a heart rate ≥ 70 bpm. This evidence comes from the SHIFT trial, which showed a reduction in HF hospitalization when patients were commenced on ivabradine due to a reduction in heart rate, however caution should be used as only 25% of patients were on optimal doses of beta-blocker [28]. Given the well-proven mortality benefits of beta-blocker therapy, these agents should be up-titrated to maximal tolerated doses prior to consideration of ivabradine initiation [29, 30]. There is weak evidence for the use of digoxin and soluble guanylate cyclase stimulator (e.g., vericiguat) in patients with progression of HFrEF despite GDMT (or who are unable to tolerate GDMT) to reduce HF hospitalizations. There is only one randomized controlled trial of digoxin in HF, which predated current GDMT. This study found no effect on mortality with digoxin but modestly reduced risk of death and hospitalization [31]. This has been supported by retrospective analyses and meta-analyses [32‐34]. The VICTORIA trial found a 10% reduction in the primary outcome (CV death or HF hospitalization) in patients with LVEF < 45%, NYHA class II-IV, on GDMT with elevated natriuretic peptides and recent HF worsening when taking vericiguat vs. placebo [35].

Loop diuretics such as frusemide or bumetanide are the preferred diuretic agent for use in most patients with HF. The ACC/AHA/HFSA guidelines also recommend the addition of a thiazide (e.g., chlorthalidone or hydrochlorothiazide) for refractory fluid retention unresponsive to high-dose loop diuretics alone. With the exception of mineralocorticoid receptor antagonists (MRA) (e.g., spironolactone), the effects of diuretics on morbidity and mortality are uncertain, but their symptomatic benefits are well established.

Both guidelines agree that implantable cardiac defibrillators (ICD) are effective at reducing sudden cardiac death (SCD), and improving cardiac function and quality of life, in selected patients with HF. For primary prevention, regardless of etiology, the ACC/AHA/HFSA guidelines strongly recommend an ICD to reduce the risk of SCD and all-cause mortality in patients with symptomatic HFrEF of ischemic or non-ischemic etiology, with an LVEF ≤ 35% despite ≥ 3 months of optimal medical management if their life expectancy is > 1 year (CoR: 1) [1].

The ESC guidelines state ICDs are strongly recommended in ischemic cardiomyopathy (CoR: 1), but are only reasonable to consider in non-ischemic etiology (CoR: 2a) [4]. These conclusions are based on several studies. The MADIT-II trial specifically investigated patients with previous MI, LVEF ≤ 35% with non-sustained ventricular tachycardia (VT) and found a mortality benefit of ICDs [19]. In comparison, the DEFINITE trial included only non-ischemic patients with LVEF ≤ 35% and frequent premature ventricular contractions (PVCs) or non-sustained VT, and found a non-significant mortality benefit [37]. In the SCD-HEFT trial, which included patients with ischemic and non-ischemic cardiomyopathy with an LVEF ≤ 35% and NYHA class II-III, there was a benefit with ICD compared with amiodarone or placebo alone [38]. More recently, the DANISH trial, which only enrolled patients with non-ischemic cardiomyopathy and LVEF ≤ 35% to ICD or standard care found no reduction in total mortality despite a modest absolute risk reduction in sudden death [39]. The ACC/AHA/HFSA guideline authors questioned the significance of this result as 58% of patients in each limb received CRT, potentially mitigating the benefit of an ICD [1].

Cardiac resynchronization therapy (CRT) is strongly recommended for symptomatic patients (NYHA class II-IV on best medical management) who have LVEF ≤ 35%, sinus rhythm, left bundle branch block (LBBB) with a QRS of ≥ 150 ms to reduce total mortality and hospitalizations, and improve symptoms and quality of life (CoR: 1). These findings were shown in the MIRACLE trial, COMPANION trial, CARE-HF trial, REVERSE trial, and RAFT trial [40‐44]. In patients without a LBBB or QRS duration between 130 and 149 ms, the available evidence for CRT demonstrates a moderate level of certainty (CoR: 2a) [40, 42‐45]. The evidence is uncertain for patients who are asymptomatic (CoR: 2b) [45].

ACC/AHA/HFSA guidelines state that CRT is not recommended when QRS is < 120 ms, compared with < 130 ms in the ESC guidelines. In addition, ACC/AHA/HFSA guidelines find CRT reasonable if the LVEF is 36–50% and the patient has high degree atrioventricular block, based on the BLOCK-HF trial [46].

These variations in recommendations highlight the nuanced interpretation of available evidence. It is important for healthcare professionals to consider the specific patient characteristics and individualize the decision-making process when determining the appropriateness of CRT for patients.

Both the ACC/AHA/HFSA and ESC guidelines emphasize the critical role of a multidisciplinary team (MDT) approach in the management of HF. These guidelines recognize the value of involving various healthcare professionals, including cardiologists, nurses, pharmacists, dieticians, mental health clinicians, social workers, primary care clinicians, and additional specialists. Both guidelines assign the highest level of evidence (CoR: 1) to support the implementation of an MDT approach.

The inclusion of an MDT approach in the 2022 guidelines is emphasized significantly compared to previous recommendations. It acknowledges the role of non-pharmacological interventions, such as dietary modifications, fluid management, and exercise, alongside the prescription and adherence to GDMT.

By adopting an MDT approach, healthcare professionals can collectively address the multifaceted aspects of HF management. This collaborative approach enables comprehensive patient care, optimized non-pharmacological strategies, and ensures appropriate implementation of GDMT in accordance with the guidelines.

The guidelines differ slightly on the recommendations for telemonitoring. The ACC/AHA/HFSA guidelines suggests that telemonitoring is not recommended, however, and that further research is required. The ESC guidelines suggest telemonitoring may be reasonable to reduce the risk of recurrent CV and HF hospitalizations, and CV death (CoR: 2b). Emerging data have shown promise in smartphone-based options for telemonitoring [47], and this is likely to be a focus in future guidelines.

Both guidelines highlight that no prospective randomized controlled trials (RCTs) have been performed specifically for patients with HFmrEF, although there is evidence from subgroup analysis or post hoc analysis from previous HF trials. As such, strong recommendations cannot be made. ACC/AHA/HFSA and ESC guidelines both suggest that ACEi, ARB, or ARNi in addition to beta-blocker and MRA may be considered to reduce risk of HF hospitalizations and death (CoR: 2b). These recommendations are new since previous guidelines. The BBmeta-HF trial [48] found beta-blockers reduced all-cause mortality and CV mortality in patients with HFmrEF. Similarly, PARAGON-HF trial for patients with LVEF 45–57% suggested benefit of sacubitril-valsartan versus valsartan alone [49]. Subgroup analysis of patients with HFmrEF from the CHARM trial found candesartan reduced the risk of CV death and HF hospitalization [50]. The TOPCAT trial found spironolactone reduced the risk of the primary composite endpoint of CV death, HF hospitalization or resuscitated sudden death in patients with HFmrEF on subgroup analysis [51].

The ACC/AHA/HFSA guideline finds stronger evidence for SGLT2i to be beneficial in decreasing HF hospitalizations (CoR: 2a), whereas the ESC guidelines do not include them for HFmrEF. There are no significant trials for ICD or CRT in patients with HFmrEF and are therefore not recommended.

Both guidelines agree that there are no treatments that have been shown to reduce mortality in patients with HFpEF. There are, however, marginal benefits on HF hospitalizations for some pharmacological treatments, specifically diuretics and SGLT2i. These recommendations are primarily based on the EMPEROR-Preserved, TOPCAT, CHARM, and PARAGON-HF trials [49‐52]. Both the ACC/AHA/HFSA 2022 HF guideline and the ESC 2021 HF guideline recommend diuretics to reduce congestion and improve symptoms.

New recommendations for treatment for HFpEF from the ACC/AHA/HFSA 2021 guidelines include the use of SGLT2i based on the recent EMPEROR-Preserved trial, which demonstrated a reduction in the composite outcome of CV death or hospitalization in patients on empagliflozin (n = 2997) vs. placebo (2991) who had HFpEF and a NYHA II-IV and had been hospitalized with HF in the last 12 months (CoR: 2a) [52]. The benefit was similar irrespective of their diabetes status. The ACC/AHA/HFSA guidelines also suggest ARB, ARNi, and MRAs can be considered (CoR: 2b). This is in contrast to the ESC guidelines where SGLT2i are indicated in patients with type 2 diabetes mellitus only (CoR: 1). This difference is likely due to the timing of publication, as ESC guidelines were published at a similar time to the EMPEROR-Preserved trial [52]. Recently, the ACC released an expert consensus decision pathway for management of HFpEF, which highlights GDMT in more detail [53].

The ACC/AHA/HFSA guidelines recommend all patients with HF should receive palliative and supportive care to improve quality of life (CoR:1), with the suggestion that patients’ who have stage D HF, uncontrolled symptoms, multimorbidity, frailty, or cognitive impairment be referred to specialist palliative care (CoR:2a). There is no such suggestion in the ESC guidelines. Both the ACC/AHA/HFSA and ESC guidelines support the use of inotropes in the palliative setting for symptom relief (CoR: 2b). These recommendations are echoed in the ESC guideline, however the evidence has not been assessed.