Sacubitril/Valsartan for Heart Failure With Preserved Ejection Fraction and Resistant Hypertension

One Shot for a Double Strike?

Massimo Volpe; Giovanna Gallo


Eur Heart J. 2021;42(36):3753-3755. 

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 κ-light chain enhancer of activated B cells; NEP, neprilysin; NP, natriuretic peptide; RAAS, renin–angiotensinaldosterone system; SNS, sympathetic nervous system; T NF-α, tumour necrosis factor-α.

The management of resistant hypertension and the treatment of heart failure with preserved ejection fraction (HFpEF) still represent two burning 'unmet needs' in the field of cardiovascular disease.[1–3] Although the prevalence of these conditions has been constantly increasing over the last decades, therapeutic strategies are frequently insufficient in spite of the continuous scientific efforts to explore new pharmacological and non-pharmacological approaches.

The clinical relevance of these unresolved issues is even higher due to the close pathophysiological link between uncontrolled hypertension and HFpEF, the first contributing to the development of left ventricular (LV) hypertrophy, impaired ventricular and active atrial relaxation and filling capacities, increased cardiomyocyte passive stiffness, reduced arterial compliance, and abnormal ventricular–arterial coupling which finally lead to LV diastolic dysfunction and eventually to HFpEF.[4] As a matter of fact, hypertension and HFpEF co-exist in >95% of subjects,[5] and a large proportion of HFpEF patients have uncontrolled blood pressure (BP) levels despite the use of multiple antihypertensive drugs. Indeed, resistant hypertension, defined as the failure to achieve recommended BP targets despite appropriate lifestyle measures and treatment with optimal or best-tolerated doses of three or more drugs which should include a diuretic [typically an angiotensin-converting enzyme inhibitor (ACEi) or an angiotensin receptor blocker (ARB) and a calcium channel blocker (CCB)],[1,6] accounts for 10–20% of HFpEF patients.[7]

In the current issue of the European Heart Journal, Jackson and colleagues have examined the potential effects of sacubitril/valsartan (Sac/Val), which combines angiotensin receptor blockade and neprilysin inhibition (ARNi), on BP control in HFpEF patients with apparent resistant hypertension [specifically defined as systolic BP (SBP) ≥140 mmHg or ≥135 mmHg if diabetic despite treatment with valsartan, a CCB, and a diuretic].[8]

The results originated from a post-hoc analysis of data[8] from the PARAGON-HF (Prospective Comparison of ARNI With ARB Global Outcomes in Heart Failure With Preserved Ejection Fraction) trial.[9] The highlights of this analysis may be summarized as follows:

  1. The high prevalence of resistant hypertension in HFpEF is confirmed in the current study, accounting for 15.2% of the overall population (731 patients). Moreover, 135 individuals (2.8%) failed to achieve BP control despite treatment with a mineralocorticoid receptor antagonist (MRA), suggesting 'apparent MRA-resistant' hypertension. These proportions might have been even underestimated, since patients with SBP >180 mmHg were excluded from the trial.

  2. The presence of resistant hypertension was a negative prognostic predictor in HFpEF. In fact, the rate of the primary composite outcome (total hospitalizations for HF and death from CV causes) was higher in patients with apparent resistant hypertension [17.3; 95% confidence interval (CI) 15.6–19.1 per 100 person-years], compared with those with controlled SBP (13.4; 95% CI 12.7–14.3 per 100 person-years), with an adjusted rate ratio (RR) of 1.29, 95% CI 1.05–1.58. Patients with apparent resistant hypertension also had a greater risk of the pre-specified exploratory composite of HF hospitalization, myocardial infarction, stroke, and CV death.

  3. Sac/Val appeared to be more effective than valsartan alone in treating resistant hypertension in HFpEF. Patients treated with Sac/Val 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. Consistent results were obtained in individuals with apparent MRA-resistant hypertension [–8.8 mmHg (–14.0 to –3.5 mmHg) vs. –6.3 (–12.5 to –0.1 mmHg) in the Sac/Val and valsartan groups, respectively]. Sac/Val improved the achievement of SBP control at 16 weeks by 22% compared with valsartan alone [47.9% vs. 34.3%; adjusted odds 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%, respectively, with an adjusted OR of 2.63 (95% CI 1.18–5.89).

A reasonable candidate mechanism through which neprilysin inhibition produces a more marked BP reduction is the increase of biologically active natriuretic peptides (NP) and their binding with guanylate cyclase/cGMP-coupled receptors, which mediate vasodilation and natriuresis and contribute to the inhibition and counterbalance of the renin–angiotensin–aldosterone system (RAAS), the sympathetic nervous system (SNS), endothelin, and vasopressin.[10,11] Based on this pathophysiological assumption, previous studies had investigated the potential efficacy of ARNi as antihypertensive agents.

Ruilope and colleagues demonstrated that Sac/Val provided significantly greater 8-week reductions from baseline in mean sitting diastolic and systolic BP than valsartan in a population of 1328 patients with mild and moderate hypertension. The superiority of Sac/Val was also confirmed in a subgroup of 427 patients who underwent ambulatory BP monitoring, showing significant differences in 24-h mean ambulatory SBP compared with valsartan.[12]

The BP-lowering effect of Sac/Val in HFpEF was previously evaluated also in the phase II PARAMOUNT (Prospective comparison of ARNI with ARB on Management Of heart failUre with preserved ejection fracTion) trial which randomized 301 participants to receive Sac/Val titrated to 200 mg twice daily or valsartan titrated to 160 mg twice daily. After 12 weeks of treatment, SBP reduction was significantly greater in the Sac/Val compared with the valsartan group (29.3 vs. 22.9 mmHg, respectively), these results persisting at 36 weeks.[13]

In this view, Sac/Val may represent a rational and viable therapeutic strategy in the management of resistant hypertension in HFpEF patients (Graphical Abstract), even though specifically designed randomized clinical trials are required to support this indication. Moreover, it would be interesting to explore whether the use of Sac/Val in subjects with resistant hypertension may delay or prevent the development of hypertension-mediated cardiac damage and the progression to HFpEF and some additional related issues raised by the post-hoc analysis of PARAGON-HF[9] deserve a comment.

First, patients with apparent resistant hypertension had an increased risk of cardiovascular mortality and HF rehospitalization despite lower median N-terminal-pro brain natriuretic peptide (NT-proBNP) levels compared with those with controlled BP (744 vs. 962 pg/mL, respectively). This finding may appear somewhat controversial, since higher NP levels are usually associated with worse prognosis in HF.[10] The co-existence of resistant hypertension, however, may play an independent role in influencing clinical outcomes in HFpEF, irrespective of pharmacological treatment, comorbidities, and biomarker levels. In this view, a more intensive BP-lowering strategy may effectively contribute to reduce outcomes in patients with HFpEF.

Secondly, the relative proportion of responders was larger in patients with apparent MRA-resistant hypertension; this probably reflects complementary mechanisms of action of MRA and ARNi.[11] If these results should be confirmed by dedicated studies, it could be considered a reasonable attempt to add Sac/Val in patients who fail to achieve recommended BP targets despite the maximum tolerated dose of spironolactone or other MRA agents.[6,14]

Finally, although Sac/Val did not reduce the risk of the primary endpoint in the overall population of the PARAGON trial[9] (RR 0.87; 95% CI 0.75–1.01; P = 0.06), its effects on clinical outcomes were not analysed in the hypertensive subgroups.[8] Indeed, in the HFpEF population of PARAGON-HF, 41.6% of recruited patients were hypertensive and 15.2% had resistant hypertension. This relevant proportion of HFpEF patients with hypertension may benefit from Sac/Val treatment, though this hypothesis needs to be proven. On the other hand, the action of Sac/Val may be less relevant in patients with different prevalent aetiologies of HFpEF, such as diabetes, obesity, renal dysfunction, or amyloidosis.[15]

In view of the wide heterogeneity of phenotypes in patients with HFpEF and of the consequent limits of a therapeutic strategy based on a 'one-size-fits-all' approach, which has been repeatedly chased in multiple clinical trials over the last two decades, more selected studies on specific phenotypes of HFpEF (including difficult-to-treat and resistant hypertension) should be encouraged.

The current analysis performed by Jackson et al.[8] supports such an approach as it documents better control of BP and potentially better outcomes in patients with resistant hypertension and HFpEF when treated with Sac/Val. This paves the way to more formal prospective studies to investigate the potential double hit benefits of Sac/Val in a tough and challenging clinical field such as resistant hypertension and HFpEF.