Is Combination Therapy the Key for Treatment of Heart Failure With Mid-Range or Preserved Ejection Fraction?

Heart failure (HF) is a major clinical syndrome that is a leading cause of death and morbidity,^1,2 and is closely associated with neurohormonal activation.³ The left ventricular ejection fraction (LVEF) is widely used to guide treatment for patients with HF, predominantly because of previous clinical trial inclusion criteria, as the studies that reported beneficial effects of treatment mostly included patients with HF and reduced LVEF (HFrEF). However, given that HFrEF accounts for only 30–40% of all patients with HF, it is undoubtedly important to develop treatment guidelines for patients with preserved LVEF.

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Numerous randomized controlled trials (RCTs) targeting HF with preserved EF (HFpEF) have failed to show prognostic benefit, except for the EMPEROR-Preserved trial (Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Preserved Ejection Fraction)⁴ (Table 1). Moreover, some subgroup analyses of RCTs showed possible benefit of neurohormonal blockade on HF with mid-range EF (HFmrEF), even though no prospective RCT has focused exclusively on patients with HFmrEF (Table 2). The retrospective analysis of the CHARM (The Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity) Programme trial reported that candesartan reduced cardiovascular death or HF hospitalization in patients with HFmrEF.⁵ Furthermore, a meta-analysis of 11 major RCTs revealed that the use of β-blockers was significantly associated with a lower incidence of cardiovascular death in patients with HFmrEF and sinus rhythm.⁶ However, there have been no studies on the clinical benefit of initiation of combination therapy for neurohormonal blockade in patients hospitalized with HFmr/pEF.

Table 1. Major Randomized Controlled Trials Focusing on Heart Failure With Preserved Ejection Fraction

Study name	Year published	Treatment	Sample size (n)	LVEF	Main outcomes	Hazard ratio (95% CI)	Follow-up period
ACE-I/ARB
CHARM- Preserved	2003	Candesartan vs. placebo	3,023	>40%	CV death or hospitalization for HF	0.89 (0.77–1.03)	Median: 36.6 months
PEP-CHF	2006	Perindopril vs. placebo	850	≥40%	ACD or unplanned HF hospitalization	0.92 (0.70–1.21)	Mean: 26.2 months
I-PRESERVED	2008	Irbesartan vs. placebo	4,128	≥45%	ACD or hospitalization for CV events	0.95 (0.86–1.05)	Mean: 49.5 months
β-blockers
J-DHF	2013	Carvedilol vs. placebo	245	>40%	CV death or hospitalization for HF	0.90 (0.54–1.49)	Mean: 3.2 years
MRA
TOPCAT	2014	Spironolactone vs. placebo	3,445	≥45%	CV death or hospitalization for HF	0.89 (0.77–1.04)	Mean: 3.3 years
Digitalis
DIG-PEF	2006	Digoxin vs. placebo	988	>45%	CV death or hospitalization for HF	0.82 (0.63–1.07)	Median: 37 months
ARNI
PARAGON-HF	2019	Sacubitril/valsartan vs. valsartan	4,882	≥45%	CV death or total hospitalization for HF	0.87 (0.87–1.01)	Median: 35 months
SGLT2-i
EMPEROR- Preserved	2021	Empagliflozin vs. placebo	5,988	>40%	CV death or hospitalization for HF	0.79 (0.69–0.90)	Median: 36.2 months

ACD, all-cause death; ACE-I, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; ARNI, angiotensin-receptor neprilysin inhibitor; CI, confidence interval; CV, cardiovascular; HF, heart failure; LVEF, left ventricular ejection fraction; MRA, mineralocorticoid receptor antagonist; SGLT2-i, Sodium-glucose cotransporter 2 inhibitor.

Table 2. Sub- or Meta-Analysis of Randomized Controlled Trials for Heart Failure With Mid-Range Ejection Fraction

Study name/type	Year published	Treatment	Sample size (n)	LVEF	Main outcomes	Hazard ratio (95% CI)
ARB
CHARM-Programme (subanalysis)	2018	Candesartan vs. placebo	1,322	40–49%	CV death or hospitalization for HF	0.76 (0.61–0.96)
β-blockers
Meta-analysis of 11 RCTs	2018	β-blockers vs. placebo	575	40–49%	ACD CV death	ACD: 0.59 (0.34–1.03) CV death: 0.48 (0.24–0.97)
MRA
TOPCAT (subanalysis)	2016	Spironolactone vs. placebo	520	40–49%	CV death, aborted cardiac arrest or hospitalization for HF	All cohort: 0.72 (0.50–1.05) Americans: 0.55 (0.33–0.91)
ARNI
PARADIGM-HF + PARAGON-HF (subanalysis)	2020	Sacubitril/valsartan vs. enalapril or valsartan	1,427	42.5–52.5%	CV death or first hospitalization for HF	0.89 (0.73–1.10)
SGLT2-i
EMPEROR-Preserved (subanalysis)	2021	Empagliflozin vs. placebo	1,983	40–49%	CV death or hospitalization for HF	0.71 (0.57–0.88)
sGC stimulators
VICTORIA (subanalysis)	2020	Vericiguat vs. placebo	720	40–45%	CV death or first hospitalization for HF	1.05 (0.81–1.36)

sGC, soluble guanylate cyclase. Other abbreviations as in Table 1.

In this issue of the Journal, Seko et al⁷ investigate the clinical effect of combination therapy (angiotensin-converting enzyme inhibitors (ACE-I)/angiotensin II receptor blockers (ARB) and β-blockers) in 858 patients hospitalized with HFmr/pEF and not receiving ACE-I/ARB or β-blockers on admission. They found that initiation of both ACE-I/ARB and β-blockers during the index hospitalization was significantly related to a lower risk of all-cause death or HF readmission compared with those who did not receive ACE-I/ARB or β-blockers. The authors conclude that early initiation of combination therapy could lead to improved prognosis of patients hospitalized with HFmr/pEF. Nevertheless, the prescription of either ACE-I/ARB or β-blockers did not achieve significant clinical benefit, and the results were consistent between HFmrEF and HFpEF.

As the sympathetic nervous system and the renin-angiotensin-aldosterone system are activated in a substantial proportion of patients with HFmr/pEF, as well as HFrEF,⁸ neurohormonal blockade would theoretically be effective for HFmr/pEF. However, the efficacy of HF drugs has been limited partially due to the pathologic heterogeneity in patients with HFmr/pEF. Therefore, blockage of multiple pathways that relate to the pathophysiological background of HF could be even more important for HFmr/pEF. To date, several studies have investigated the beneficial effect of the combination of neurohormonal antagonists for HFmr/pEF, but the results have been inconsistent. Miura et al reported that adding olmesartan to β-blockers in hypertensive patients with stable HFpEF was significantly associated with a decreased incidence of all-cause death compared with those on β-blockers alone.⁹ Conversely, another clinical study involving patients hospitalized with HFmr/pEF revealed that the combination of ACE-I/ARB and β-blockers at discharge did not reduce all-cause death or HF readmission.¹⁰ Moreover, data from 45 Spanish hospitals with 3,348 patients hospitalized with HFpEF demonstrated that the combination of ACE-I/ARB and β-blockers at discharge was significantly associated with increased risk of all-cause death and worsening HF.¹¹ However, these studies did not examine the clinical benefits of early initiation of combination therapy during hospitalization.

Another important finding from the study by Seko et al is the possible beneficial effect of the early initiation of combination therapy. Recently, a simultaneous or rapid sequence initiation approach has attracted much attention¹² because the advantageous effect of the neurohormonal antagonists appears from a very early stage after their initiation. Moreover, a Swedish nationwide registry reported that prescription of 2 drug classes (ACE-I/ARB/angiotensin-receptor-neprilysin inhibitor and β-blockers) at 50–99% of the target dose was associated with a lower risk of cardiovascular death or hospitalization for HF compared with only 1 drug class at 100% of the target dose in patients with HFrEF.¹³ Therefore, early administration of multiple drugs, even in small doses, may be preferable in terms of prognosis.

However, many uncertainties persist, especially regarding the diagnosis of HFmr/pEF. For instance, most of the previous clinical studies have not excluded the possibility of cardiomyopathy, such as cardiomyopathy caused by cardiac amyloidosis, despite recent studies showing that it is not rare. Moreover, previous longitudinal studies have reported that it is not uncommon for LVEF to dynamically change and shift from 1 category to another.¹⁴ In addition, quantification of LVEF by echocardiography is subject to considerable inter- and intra-observer variability. These findings imply that it is quite challenging to identify “true” HFmr/pEF patients, which makes it difficult to perform RCTs to find a specific treatment for HFmr/pEF despite the importance of performing clinical trials for this population.

Taken together, the results of studies including the present study support the idea that early initiation of multiple antineurohormonal medications during hospitalization for patients with HFmr/pEF who are naïve to these drugs is safe and also potentially favorable in terms of outcomes. Nevertheless, in future research we need to find a better way to diagnose HF that can guide our management and leads to a better prognosis for patients.

Conflicts of Interest

Y.M. received an honorarium from Otsuka Pharmaceutical Co., Novartis Japan, and Bayer Japan, and collaborative research grants from Pfizer Inc. and Nippon Boehringer Ingelheim Co. Other authors have nothing to declare.

Disclosure

T.M. is an Associate Editor of Circulation Journal.

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