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Heart failure (with preserved ejection fraction (HFpEF) is a major global health issue. Indeed, with the ageing of the population, its prevalence is growing, affecting between 1.1% and 5.5% of the global population, and accounting for 50% of HF cases.
HFpEF: a difficult diagnosis
HFpEF is a complex clinical syndrome with a large variety of phenotypes. Its definition is not simple, with no gold standard, making the diagnosis sometimes challenging for the clinician, and explaining therefore the heterogeneity of patients included in the different studies. HFpEF is characterised by symptoms and signs of HF associated with a normal or nearly normal left ventricular ejection fraction. The definition of ‘preserved’ ejection fraction (EF) in previous clinical trials was not homogeneous, with cut-off values varying from 40% to 50%. The latest European Society of Cardiology (ESC) guidelines have chosen a cut-off value of ≥50% and have created a new category called HF with mid-range ejection fraction. In order to establish the diagnosis, these guidelines also require the presence of elevated natriuretic peptides and objective evidence of other cardiac functional and structural alteration underlying HF (left atrial enlargement or left ventricular hypertrophy). Diastolic dysfunction, mainly assessed by echocardiography-derived measurement, is also a major element of this diagnosis. In doubtful cases, a ‘diastolic stress test’ or invasively measured elevated LV filling pressure might be helpful1 (figure 1).
A difficult treatment due to diverse phenotypes?
In the last decades, the use of inhibition of the renin-angiotensin-aldosterone system (RAAS), beta-blockage and device therapy has resulted in a decrease in mortality in patients with HFpEF. Nevertheless, in HFpEF there is still no validated therapy as no treatment has convincingly shown its efficacy to reduce mortality or morbidity. This makes the management of these patient challenging and sometimes frustrating. The ESC guidelines only recommend the use of diuretics to relieve symptoms and to screen these patients for comorbidities and to treat them accordingly1 (figure 1). In the 2017 updated American College of Cardiology (ACA) American Heart Association (AHA) Heart Failure Society of America (HFSA) guidelines, beta-blockers, ACE inhibitors and angiotensin receptor blockers (ARBs) are recommended in patients with hypertension, ARBs might be considered to reduce hospitalisation and aldosterone receptor antagonist could be used and in selected patients.2
In their Heart publication, Zheng et al 3 report the results of a meta-analysis on the effects of drugs on outcome in HFpEF. The main finding is that drug therapies did not significantly decrease all-cause or cardiovascular mortality, but decreased hospitalisations for HF. When looking at the specific effect of the different HF treatment, beta-blockers showed a reduction in all-causes and cardiovascular mortality. On the opposite, RAAS blockade demonstrated no effect on mortality, but demonstrated a decrease in HF hospitalisation.
This meta-analysis conveys important and pertinent messages to all physicians in charge of patients with HFpEF. As regards the use of beta-blocker therapy, two previous controlled trials were negative4 5 whereas one was positive.6 Many factors may explain this discrepancy, the differences in the phenotype of the patients with HFpEF might be one of them. Indeed, one of the underlying pathophysiological background to use beta-blockers is to improve diastolic filling with the decrease of heart rate, but also to prevent ischaemia.5 The difference in prior myocardial infarction (MI) (respectively 50% in SENIORS5 and 100% in the study by Aronow et al 6) might therefore explain the variable benefit as beta-blockers have demonstrated prognostic benefits in post-MI patients.7
This is only one example of the influence of considering the diversity of phenotype of HFpEF. The clinical management and future clinical trial in HFpEF could probably benefit from a phenotype-specific approach rather than a ‘one-size-fits-all’ tactic. Precision medicine is already well established in modern cancer care and should be implemented in the field of cardiology. This is particularly true in HFpEF as the pathophysiology underlying HFpEF is heterogeneous and associated with different phenotypes which include concomitant cardiovascular diseases (arterial hypertension, atrial fibrillation, coronary artery disease, pulmonary hypertension) and non-cardiovascular diseases (obesity, diabetes, anaemia, chronic kidney disease and chronic obstructive pulmonary disease). These conditions should be screened carefully, managed with interventions that have been shown to improve symptoms or outcome and not to exacerbate HF. Still using the example of beta-blockers therapy, this treatment might be particularly useful in case of prior MI and to control heart rate in permanent atrial fibrillation, but might be detrimental in patients in which exercise dyspnoea is explained by chronotropic insufficiency, a frequent finding in patients with HFpEF.
An appropriate end point selection
A different end point selection might also improve the results of clinical trials and might also aid in clinical management. Indeed, patients with typical HFpEF are rather old with numerous disabling comorbidities. The prevalence of non-cardiac death accounts for up to 20%–30% of deaths in HFpEF trials.8 Thus, the widely accepted all-cause mortality end point might not be optimal for HFpEF trials as it might be influenced by these comorbidities. In addition, also the patients might prefer to gain quality versus quantity of life.
In conclusion, the results of the different HFpEF trials as summarised in this meta-analysis should probably not been seen as failures. A careful evaluation of the patient, including the non-cardiovascular comorbidities, is particularly mandatory in this population in order to determine the best management and improve their symptoms, quality of life and reduce mortality.
Contributors FS and ED worked together on the manuscript. The quantify of work was identical between them.
Competing interests None declared.
Provenance and peer review Commissioned; internally peer reviewed.
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