European Heart Journal (2021) 00, 1–3 EDITORIAL

doi:10.1093/eurheartj/ehab489

Sacubitril/valsartan for heart failure with

preserved ejection fraction and resistant

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hypertension: one shot for a double strike?
Massimo Volpe * and Giovanna Gallo
Cardiology Unit, Department of Clinical and Molecular Medicine, Faculty of Medicine and Psychology, Sapienza University of Rome, Sant’Andrea Hospital, Rome, Italy

This editorial refers to ‘Sacubitril–valsartan as a treatment for apparent resistant hypertension in patients with heart failure
and preserved ejection fraction (HFpEF)’, by A.M. Jackson et al., doi:10.1093/eurheartj/ehab499.

Graphical abstract Sacubitril/valsartan as a therapeutic strategy for HFpEF and resistant hypertension. Sacubitril/valsartan inhibits both
neprilysin and angiotensin II receptor type 1, which play a role in the development of resistant hypertension and of heart failure with preserved
ejection fraction, in a vicious circle also involving vascular and microcirculatory dysfunction, neurohormonal imbalance, inflammation, and oxidative
stress. AngII, angiotensin II; AT1R, angiotensin II type 1 receptor; BH4, tetrahydrobiopterin; ET-1, endothelin 1; HFpEF, heart failure with preserved
ejection fraction; LV, left ventricle; NFKB, nuclear factor j-light chain enhancer of activated B cells; NEP, neprilysin; NP, natriuretic peptide; RAAS,
renin–angiotensinaldosterone system; SNS, sympathetic nervous system; T NF-a, tumour necrosis factor-a.

The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.
* Corresponding author. Cardiology Unit, Department of Clinical and Molecular Medicine, Faculty of Medicine and Psychology, Sapienza University of Rome, Sant’Andrea
Hospital, Rome, Italy. Email: massimo.volpe@uniroma1.it
Published on behalf of the European Society of Cardiology. All rights reserved. VC The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.
2 Editorial

.. 12.5 to –0.1 mmHg) in the Sac/Val and valsartan groups, respectively].

The management of resistant hypertension and the treatment of ..
heart failure with preserved ejection fraction (HFpEF) still represent .. Sac/Val improved the achievement of SBP control at 16 weeks by
..
two burning ‘unmet needs’ in the field of cardiovascular disease.1–3 .. 22% compared with valsartan alone [47.9% vs. 34.3%; adjusted odds
Although the prevalence of these conditions has been constantly .. ratio (OR) 1.78; 95% CI 1.30–2.43]. In patients with apparent MRA-
.. resistant hypertension, the proportions were 43.6% vs. 28.4%, re-
increasing over the last decades, therapeutic strategies are frequently ..
insufficient in spite of the continuous scientific efforts to explore new .. spectively, with an adjusted OR of 2.63 (95% CI 1.18–5.89).
..
pharmacological and non-pharmacological approaches. .. A reasonable candidate mechanism through which neprilysin inhib-
The clinical relevance of these unresolved issues is even higher due ..
.. ition produces a more marked BP reduction is the increase of bio-

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to the close pathophysiological link between uncontrolled hyperten- .. logically active natriuretic peptides (NP) and their binding with
sion and HFpEF, the first contributing to the development of left ven- ..
.. guanylate cyclase/cGMP-coupled receptors, which mediate vasodila-
tricular (LV) hypertrophy, impaired ventricular and active atrial .. tion and natriuresis and contribute to the inhibition and counterbal-
relaxation and filling capacities, increased cardiomyocyte passive stiff-
..
.. ance of the renin–angiotensin–aldosterone system (RAAS), the
ness, reduced arterial compliance, and abnormal ventricular–arterial ..
.. sympathetic nervous system (SNS), endothelin, and vasopressin.10,11
coupling which finally lead to LV diastolic dysfunction and eventually ..
.. Based on this pathophysiological assumption, previous studies had
to HFpEF.4 As a matter of fact, hypertension and HFpEF co-exist in
.. investigated the potential efficacy of ARNi as antihypertensive agents.
>95% of subjects,5 and a large proportion of HFpEF patients have un- ..
.. Ruilope and colleagues demonstrated that Sac/Val provided signifi-
controlled blood pressure (BP) levels despite the use of multiple anti-
.. cantly greater 8-week reductions from baseline in mean sitting dia-
hypertensive drugs. Indeed, resistant hypertension, defined as the ..
.. stolic and systolic BP than valsartan in a population of 1328 patients
failure to achieve recommended BP targets despite appropriate life-
.. with mild and moderate hypertension. The superiority of Sac/Val was
style measures and treatment with optimal or best-tolerated doses ..
of three or more drugs which should include a diuretic [typically an .. also confirmed in a subgroup of 427 patients who underwent ambula-
.. tory BP monitoring, showing significant differences in 24-h mean am-
angiotensin-converting enzyme inhibitor (ACEi) or an angiotensin re- ..
ceptor blocker (ARB) and a calcium channel blocker (CCB)]1,6, .. bulatory SBP compared with valsartan.12
.. The BP-lowering effect of Sac/Val in HFpEF was previously eval-
accounts for 10–20% of HFpEF patients.7 ..
In the current issue of the European Heart Journal, Jackson and col- .. uated also in the phase II PARAMOUNT (Prospective comparison of
..
leagues have examined the potential effects of sacubitril/valsartan .. ARNI with ARB on Management Of heart failUre with preserved
(Sac/Val), which combines angiotensin receptor blockade and nepri-
.. ejection fracTion) trial which randomized 301 participants to receive
..
lysin inhibition (ARNi), on BP control in HFpEF patients with appar- .. Sac/Val titrated to 200 mg twice daily or valsartan titrated to 160 mg
ent resistant hypertension [specifically defined as systolic BP (SBP)
.. twice daily. After 12 weeks of treatment, SBP reduction was signifi-
..
>_140 mmHg or >_135 mmHg if diabetic despite treatment with val- .. cantly greater in the Sac/Val compared with the valsartan group (29.3
.. vs. 22.9 mmHg, respectively), these results persisting at 36 weeks.13
sartan, a CCB, and a diuretic].8 ..
The results originated from a post-hoc analysis of data8 from the .. In this view, Sac/Val may represent a rational and viable therapeutic
..
PARAGON-HF (Prospective Comparison of ARNI With ARB .. strategy in the management of resistant hypertension in HFpEF
Global Outcomes in Heart Failure With Preserved Ejection Fraction) .. patients (Graphical Abstract), even though specifically designed
..
trial.9 The highlights of this analysis may be summarized as follows: .. randomized clinical trials are required to support this indication.
.. Moreover, it would be interesting to explore whether the use of Sac/
i. The high prevalence of resistant hypertension in HFpEF is confirmed ..
in the current study, accounting for 15.2% of the overall population
.. Val in subjects with resistant hypertension may delay or prevent the
.. development of hypertension-mediated cardiac damage and the pro-
(731 patients). Moreover, 135 individuals (2.8%) failed to achieve BP ..
control despite treatment with a mineralocorticoid receptor antag- .. gression to HFpEF and some additional related issues raised by the
..
onist (MRA), suggesting ‘apparent MRA-resistant’ hypertension. .. post-hoc analysis of PARAGON-HF9 deserve a comment.
These proportions might have been even underestimated, since .. First, patients with apparent resistant hypertension had an
patients with SBP >180 mmHg were excluded from the trial.
..
.. increased risk of cardiovascular mortality and HF rehospitalization
ii. The presence of resistant hypertension was a negative prognostic .. despite lower median N-terminal-pro brain natriuretic peptide (NT-
predictor in HFpEF. In fact, the rate of the primary composite out- ..
.. proBNP) levels compared with those with controlled BP (744 vs. 962
come (total hospitalizations for HF and death from CV causes) was ..
higher in patients with apparent resistant hypertension [17.3; 95% .. pg/mL, respectively). This finding may appear somewhat controver-
confidence interval (CI) 15.6–19.1 per 100 person-years], compared
.. sial, since higher NP levels are usually associated with worse progno-
..
with those with controlled SBP (13.4; 95% CI 12.7–14.3 per 100 .. sis in HF.10 The co-existence of resistant hypertension, however, may
person-years), with an adjusted rate ratio (RR) of 1.29, 95% CI 1.05– .. play an independent role in influencing clinical outcomes in HFpEF, ir-
..
1.58. Patients with apparent resistant hypertension also had a greater .. respective of pharmacological treatment, comorbidities, and bio-
risk of the pre-specified exploratory composite of HF hospitalization, .. marker levels. In this view, a more intensive BP-lowering strategy may
myocardial infarction, stroke, and CV death.
..
.. effectively contribute to reduce outcomes in patients with HFpEF.
iii. Sac/Val appeared to be more effective than valsartan alone in treating ..
resistant hypertension in HFpEF. Patients treated with Sac/Val .. Secondly, the relative proportion of responders was larger in
.. patients with apparent MRA-resistant hypertension; this probably
achieved a 4.8 mmHg SBP reduction (–7.0 to –2.5 mmHg) compared ..
with –3.9 mmHg (–6.6 to –1.3 mmHg) in the valsartan group. .. reflects complementary mechanisms of action of MRA and ARNi.11 If
Consistent results were obtained in individuals with apparent MRA-
.. these results should be confirmed by dedicated studies, it could be
..
resistant hypertension [–8.8 mmHg (–14.0 to –3.5 mmHg) vs. –6.3 (– . considered a reasonable attempt to add Sac/Val in patients who fail
Editorial 3

..
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analysed in the hypertensive subgroups.8 Indeed, in the HFpEF popu- .. Leonetti G, Mancia G, Pessina AC, Salvetti A, Trimarco B, Volpe M, Grassivaro
.. N, Vargiu G. Left ventricular diastolic dysfunction in elderly hypertensives: results
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on a ‘one-size-fits-all’ approach, which has been repeatedly chased in

.. G, Lund LH, Maggioni AP, Pfeffer MA, Rouleau JL, Saraiva JF, Senni M, Vardeny
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