What's all the fuss about a new guideline?

A lot has happened in the field of heart failure (HF) between the 2016 European Society of Cardiology/Heart Failure Association (ESC/HFA) guidelines and the 2021 version.1 Even in the 6 months since the 2021 version came out in full we have a major new trial, the first positive outcome trial in HF with preserved ejection fraction (HFpEF) – EMPEROR-Preserved.2, 3 In the last 3 years, we have seen the development of the first major new drug class for the management of HF whose actions are not primarily neuro-hormonally mediated – the sodium–glucose cotransporter 2 inhibitor (SGLT2i) class. The clinical guideline writing process is a slow and arduous one, so it is not surprising that the guidelines lag somewhat behind the trial evidence upon which they depend. Thus, it is of interest when one of the major international guidelines is first presented. Despite the fact the most recent ESC/HFA guideline was only published less than a year ago and it was the first of the major international guidelines to recommend the SGLT2i class and introduce the concept of the ‘foundational four’ classes of drugs to be offered to all patients with HF with reduced ejection fraction (HFrEF), it was soon behind the trial evidence because it had no drug therapy recommendation to change the outcome of HFpEF. Thus, the first update for many years of a full American guideline (American College of Cardiology/American Heart Association/Heart Failure Society of America [ACC/AHA/HFSA]) is of major interest. What we all like to see is what changes have been incorporated based on newly published trials and what previously well evaluated therapies have their place questioned due to new evidence, or even perhaps changing sentiment even when no new trials have emerged. We all like to see what new advice is on offer to guide us in managing the health of our HF patients. Whilst it is difficult to summarize such an extensive and impressive body of work, I will provide a personal perspective on what I think are the significant (or surprising) changes that have been implemented (or not), by our American colleagues, including those where they come closer to the European position, and also interestingly those where they moved in a different direction. Firstly, what are the differences and what are the similarities between the European guidelines and the American guidelines? The guideline writing group is similar and both now include two patient representatives along with both HF and other multidisciplinary experts. The class I, IIa, IIb and III recommendations are similar to both guidelines but the level of evidence is slightly more granular for the American guidelines incorporating whether the evidence is based on randomized controlled trials, expert opinion or other forms of evidence. One of the biggest changes we all expected to see in the 2022 ACC/AHA/HFSA HF guidelines was a major new emphasis on the management of HFpEF given that for the first time a drug has been proven to benefit clinical outcomes in HFpEF, beyond symptom control or comorbidity management. In this regard, the changes in the 2022 guidelines were more modest than revolutionary, with 22 pages devoted to HFrEF, one and a half to HF with mildly reduced ejection fraction (HFmrEF), and only two to HFpEF. We all know that the EMPEROR-Preserved trial was positive but it came out on the day the European guidelines were first published and therefore could not have been referred to. Thus, this new 2022 American guidelines is the first that had the opportunity to make recommendations concerning empagliflozin in HFpEF. The recommendation that came out was a little bit surprising in that they recommended SGLT2i as a class and not empagliflozin as an individual drug, and only with a relatively modest 2a B-R recommendation with the words ‘In patients with HFpEF, SGLT2i can be beneficial in decreasing HF hospitalizations and cardiovascular mortality’. Whilst many of us are expecting the dapagliflozin trial in HFpEF (DELIVER)4 to be positive, it was surprising the first ever proven drug with unequivocal benefit was not called out by name, especially as even for much older drug classes – beta-blockers (BBs) and mineralocorticoid receptor antagonists (MRAs) – the effective trial-proven drugs are specifically named (even in the case of BBs omitting one proven drug nebivolol because it had never been approved in the United States for HFrEF). Many of us expect that if DELIVER is positive in a similar manner to EMPEROR-Preserved the recommendation for these two specific SGLT2is to be elevated to class 1A. Another point that may sound pedantic, but matters, is that the American guidelines suggest for EMPEROR-Preserved ‘there was a signal for lower benefit on the primary composite endpoint, first and recurrent hospitalizations for HF at higher LVEFs >62.5%’, which is incorrect as the primary endpoint in the original publication did not have any significant left ventricular ejection fraction (LVEF) interaction. What they quote actually only came from a non-prespecified sub-group analysis of a secondary endpoint,5 and as a result it appears to have been given a somewhat undue emphasis in a guideline document. Surely, the authors are not suggesting we should keep back this novel and first ever proven therapy for our HFpEF based on such an hypothesis-generating analysis? In the staging of HF section, the American guidelines more emphasize the ACC/AHA staging system and although this was included in the recently published universal definition of HF paper,6 on the European side of the Atlantic, there is greater stress on HF being a symptomatic condition with stages A and B being better referred to as ‘at risk for HF’ or ‘pre-HF’ rather than considering them a sub-type of HF. But this difference is relatively minor. Of particularly high value are the tabular recommendations of strategies to prevent HF in both the at-risk and pre-HF categories and these include some class IA recommendations including drug therapies (such as SGLT2i in type 2 diabetes mellitus). Sub-classification of HF by LVEF ranges is recognized in both European and American guidelines and the terminology and definitions of HFrEF, HFmrEF, and HFpEF are now in concert between the two. The only difference is a fourth class HFimpEF (HF with improved ejection fraction) included in the new American guidelines. HFimpEF refers to patients who have had a documented lower LVEF in the HFrEF range but now, following improvement usually as a result of guideline-directed medical therapy (GDMT), have an ejection fraction that has increased by at least 10% and is now above 40%. Although there are very few trials in this area, there is a recommendation to maintain the usual GDMT for HFrEF in these patients long term. What else in new? These guidelines start with 10 important take-home messages and this is a good place to start when looking for what is new or what is important. As had been already stated in the European guidelines, and before that the Canadian guidelines,7 there is now a recognition of four foundational drug classes for the treatment of HFrEF, and this is repeated here, pretty much reaching an international consensus. The recommendations for the treatment of HFmrEF are substantially the same as the European guidelines with the addition of the SGLT2i class at 2a, supplementing the 2b for angiotensin receptor–neprilysin inhibitors (ARNI), angiotensin-converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARBs), MRAs, and BBs. The slightly stronger 2a recommendation for SGLT2is is mainly, one supposes, driven by the results of EMPEROR-Preserved and also the SOLOIST-WHF trial8 and other smaller trials. Another incremental addition is for the diagnostic assessment and management of amyloid heart disease now that effective treatments have emerged for transthyretin amyloid cardiomyopathy. The fact that HF is very frequently associated with significant comorbidities is also recognized by the fact now there are significant recommendations for how to manage these comorbidities in HF patients and they include recommendations on iron deficiency anaemia, hypertension, sleep disordered breathing, type 2 diabetes mellitus, atrial fibrillation, coronary artery disease and malignancy, with the last fast becoming a very hot topic given new potentially cardiotoxic cancer therapies.9, 10 This continues the trend that we have seen in guidelines over many years and in other influential publications that stress the individualization of therapies for HF.11 And there were few surprises in the recommendations that emerged, although one might be surprised the recommendation for intravenous iron did not specify the only formulation with major trial data, intravenous ferric carboxymaltose. The central algorithm for drug therapy of HFrEF is useful as it includes both the standard foundational four drug classes and diuretics as needed to relieve congestion, but then introduces later treatment options by using a “progression of HF” approach to include other options should a patient still remain very symptomatic. More options are given class I than in the European guidelines including hydralazine/nitrates in New York Heart Association (NYHA) class III–IV African American patients (class IIa in ESC/HFA guidelines) and an unequivocal class I for implantable cardioverter-defibrillator in NYHA class I–III with LVEF ≤35% instead of reducing the recommendation for non-ischaemic HF to IIa (which the ESC guidelines did in 2021, based on the DANISH trial results). Mechanical circulatory support gets a class I indication in selected patients as does palliative care, neither of which do in the ESC/HFA guidelines. When we look at the detail the American guidelines, we see they are more positive for ARNI, giving it the prime 1A recommendation for HFrEF and reserving ACEi to those where the use of ARNI is not feasible, thus giving a clear preference for ARNI then ACEi and lastly ARB if neither of the other two are feasible. Interestingly, though they still only give a 1B for ARNI as a replacement for ACEi in patients already started on therapy, recognizing that there is only a single large trial for replacement of ACEi or ARB with ARNI in patients already under treatment. One might question the 1A for ARNI use given the only positive outcomes trial was precisely in the replacement area, and not as initial therapy. An interesting addition in the American guidelines is a value statement section where recommendations on relative cost-effectiveness are made, but only where high-quality cost-effectiveness studies have been published. Another welcome feature is a wider use of a class 1A recommendation for treatments to improve functional status and quality of life (such as exercise training), whereas the European guidelines tend consider only mortality reducing therapies for the award of a class IA recommendation. Another interesting feature is a class 3 recommendation for the discontinuation of MRA to avoid life-threatening hyperkalaemia in patients whose serum potassium cannot be maintained at <5.5 mEq/L, neither advocating for, or advising against the use of novel potassium binders in the attempt to maintain lower potassium levels, instead simply saying ‘the efficacy of the use of potassium binders (e.g., patiromer, sodium zirconium cyclosilicate) to improve outcomes by facilitating continuation of MRA is uncertain’. Later in the document the novel potassium binders get a modest 2b recommendation to improve outcomes by allowing higher renin–angiotensin–aldosterone system inhibitor doses to be used. There is a very interesting and topical new section ‘GDMT Dosing: Sequencing and Up-titration’ in which class 2a advice is given of ‘In patients with HFrEF, titration and optimization of guideline-directed medications as frequently as every 1 to 2 weeks depending on the patient's symptoms, vital signs, and laboratory findings can be useful to optimize management’ expressly therefore recommending faster up-titration for the first time. And in the text the following is recommended ‘In patients with HFrEF, simultaneous initiation or sequencing, and order of guideline-directed medications are usually individualized according to patient's symptoms, vital signs, functional status, tolerance, renal function, electrolytes, comorbidities, specific cause of HF, and ability of follow-up, and does not necessarily need to be done according to the sequence of trial publications and should not be delayed’ also in an attempt to release the more rigid recommendations of prior guidelines, even though the changes are subtle and still quite conservative. Another excellent new feature is strong recommendations for systems change in health care provision with such recommendations as a 1A for “performance measures based on professionally developed clinical practice guidelines”; and 2a for “Participation in quality improvement programs, including patient registries….”, and a very interesting class 2a for standardized assessment of patient-reported health status using a validated questionnaire. These are all bringing systems processes to the attention of clinicians; gone are the days when giving drugs and performing procedures were the principal target of guideline recommendations, well in view in future will be health care systems. Conflict of interest: A.J.S.C. declares having received honoraria and/or lecture fees from AstraZeneca, Boehringer Ingelheim, Menarini, Novartis, Servier, Vifor, Abbott, Actimed, Arena, Cardiac Dimensions, Corvia, CVRx, Enopace, ESN Cleer, Faraday, Impulse Dynamics, Respicardia, Viatris.

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