Blood Pressure Reduction

Q. In clinical practice, at what stage of hypertension is sacubitril/valsartan recommended?

Clinical Evidence

In a phase 3 trial involving patients with mild-to-moderate hypertension (mean sitting systolic blood pressure [msSBP] ≥ 150 to < 180 mmHg), sacubitril/valsartan at both 200-mg and 400-mg doses demonstrated significant reductions in msSBP compared to olmesartan after 8 weeks of daily treatment. The 200-mg dose showed a more substantial decrease of − 5.0 mmHg, with statistical significance for both noninferiority and superiority. Additionally, the 400-mg dose of sacubitril/valsartan resulted in more significant reductions in msSBP, as well as in mean sitting diastolic blood pressure (msDBP) and mean sitting pulse pressure compared to olmesartan. Overall, treatment with sacubitril/valsartan proved effective, providing superior BP reduction and a higher proportion of patients achieving target BP goals compared to olmesartan in Japanese individuals with mild-to-moderate essential hypertension [23].

In a randomized controlled trial involving 1215 patients with mild-to-moderate hypertension, sacubitril/valsartan were compared to valsartan over 8 weeks. The study revealed that across various doses, sacubitril/valsartan led to significantly more significant reductions in msDBP compared to the appropriate comparator dose of valsartan (mean reduction: − 2.2 mmHg, 95% CI − 3.3 to − 1.1; P < 0.0001). Specifically, the reduction was notably different for 200-mg sacubitril/valsartan versus 160-mg valsartan and 400-mg sacubitril/valsartan versus 320-mg valsartan. This dual-acting sacubitril/valsartan demonstrated both complementary and fully additive effects on BP reduction compared to valsartan, indicating its potential as a promising treatment for hypertension and CVD [24]. The recently published study in patients with mild-to-moderate hypertension showed that ARNI induced significantly higher systolic and diastolic BP reduction in comparison with ARB (olmesartan) after only 8 weeks of treatment. Patients treated with ARNI achieved a higher BP control rate compared to those who were treated with olmesartan [23].

Expert Opinion

Clinical trials from Japan and China have demonstrated the efficacy of sacubitril/valsartan in mild and moderate hypertension. These data will require further substantiation in other ethnic populations, including Asian Indians. The more robust potential indication is that it is difficult to control hypertension where there is a significant limitation of therapeutic choices. It is imperative to achieve sustained and early BP control in difficult-to-treat hypertension where sacubitril/valsartan may fulfill an unmet need.

Potential Benefits of Sacubitril/Valsartan for Nocturnal Blood Pressure Control

Q. Can sacubitril/valsartan effectively lower nocturnal blood pressure with the early morning pre-dosing period?

Clinical Evidence

The exact cause of diurnal BP fluctuations is not yet understood. There remains a notable gap in medical care with the effective management of nocturnal hypertension, as current antihypertensive medications are typically administered only once daily, in the morning. Unfortunately, this results in a blind spot in therapeutic coverage during the early morning hours, when drug concentrations and BP-lowering effects are at their lowest before the administration of morning medication [25].

The PARAMETER (Prospective Comparison of ARNI with Angiotensin Receptor Blocker Measuring Arterial Stiffness in the Elderly) study was a 52-week multicenter trial compared the efficacy of sacubitril/valsartan 200 mg/day to olmesartan 20 mg/day in 454 patients with systolic hypertension and pulse pressure > 60 mmHg. The groups underwent force titration to double initial drug doses after 4 weeks, with primary assessment at 12 weeks. The study revealed that the differences in mean 24-h central aortic systolic pressure (CASP) and SBP were mainly attributed to more effective nighttime reductions, particularly during sleep. Sacubitril/valsartan demonstrated significantly more significant decreases in mean ambulatory CASP (− 5.2 mmHg) and MASBP (− 5.9 mmHg) during nighttime, with the essential differences of MACASP (− 6.3 mmHg) and MASBP (− 6.9 mmHg) observed in the early morning hours. The dual ARB/neprilysin inhibition provides favorable outcomes on central aortic hemodynamics, potentially offering therapeutic advantages beyond those seen in ARB alone [26].

A post hoc analysis investigated the impact of sacubitril/valsartan on 24-h BP within subgroups characterized by nocturnal BP dipping profiles. Patients received either sacubitril/valsartan (200 mg/day or 400 mg/day) or olmesartan (20 mg/day) over an eight-week treatment period. Both doses of sacubitril/valsartan demonstrated significant reductions in nighttime SBP compared to olmesartan in both the dipper and non-dipper groups sacubitril/valsartan versus olmesartan: − 4.6 [95% CI, − 7.3 to − 1.8] and − 6.8 [95% CI, − 9.5 to − 4.1] mmHg, respectively; P < 0.01 and P < 0.001). The differences in nighttime SBP were more pronounced in the non-dipper group (SBP control rate of 34.4% and 42.6% with sacubitril/valsartan 200 and 400 mg/day versus 23.1% with olmesartan 20 mg/day) [25].

Expert Opinion

The efficacy of sacubitril/valsartan in a single dose in the morning, like valsartan monotherapy, has shown efficacy in 24-h control of BP. Sacubitril/valsartan exhibits consistent antihypertensive effects across all ambulatory BP measures (24-h, daytime, and nighttime), with particularly noteworthy reductions in nighttime BP, indicating adequate BP-lowering coverage throughout the entire day, including overnight and the early morning dosing period.

Management of Salt-Sensitive Hypertension with Sacubitril/Valsartan

Q. Is sacubitril/valsartan a superior pharmacological alternative to standard-of-care therapy for patients with salt-sensitive hypertension?

Clinical Evidence

When compared with the Western population, Asian individuals typically present with higher salt intake and are more inclined to be salt-sensitive. A high intake of salt leads to unfavorable outcomes regarding the potential of RAAS blockers to lower BP [23].

The multicenter, randomized study by Wang et al. in patients with salt-sensitive hypertension showed that sacubitril/valsartan was associated with a significant short-term increase in natriuresis (adjusted treatment difference: 24.5 mmol/6 h, 50.3 mmol/24 h, both P < 0.001) and diuresis (adjusted treatment difference: 291.2 ml/6 h, P < 0.001; 356.4 ml/24 h, P = 0.002) on day 1 and superior in controlling office and ambulatory BP on day 28 versus valsartan. Further, sacubitril/valsartan administration was associated with a more significant decrease in office and ambulatory BP on day 28 and significantly reduced N-terminal pro-B-type natriuretic peptide levels on day 28 (adjusted treatment difference: − 20%; P = 0.001). This study concluded that once-daily administration of sacubitril/valsartan in the morning can be effective in office and ambulatory BP control [20].

Expert Opinion

Clinical studies in salt-sensitive hypertension are less but with positive outcomes. Considering the propensity of Asian Indians for salt-sensitive hypertension, sacubitril/valsartan may be a potential anti-hypertensive agent in this category of patients.

Impact on Cardiovascular OutcomesRole of Sacubitril/Valsartan in Cardiac Remodeling in Patients with Hypertension

Q. Can sacubitril/valsartan be recommended for cardiac remodeling in hypertensive patients?

Clinical Evidence

Several experimental and clinical studies provide evidence that hypertension is causally related to unfavorable cardiac structural changes, such as enlargement of left atrial, left ventricular (LV) hypertrophy and myocardial fibrosis [27], abnormal cardiac sympathetic nervous system, and functional changes including both LV systolic and diastolic dysfunction [28].

In a randomized, multicenter, double-blind study comparing sacubitril/valsartan and olmesartan effects on cardiovascular remodeling in hypertensive patients, the sacubitril/valsartan group exhibited significantly more significant reductions in left ventricular mass index versus the olmesartan group at both 12 weeks (− 6.4 vs. − 2.3 g/m2; P = 0.039) and 52 weeks (− 6.8 vs. − 3.6 g/m2; P = 0.029). These differences remained significant after adjustment for SBP at follow-up (P = 0.036 and 0.019 at 12 and 52 weeks, respectively), and similar signals (though formally non-significant) were observed after adjusting for changes in SBP [29].

The single-center, prospective before–after study revealed that sacubitril/valsartan treatment partially improved cardiac remodeling parameters while enhancing the life quality and reducing fatigue experienced by the patients. The peak velocities of trans-mitral early value showed a significant decrease in the 12 weeks after the initiation of sacubitril/valsartan (P = 0.026). Although the ratio of trans-mitral to mitral annular early diastolic velocity improved, it did not reach statistical significance (14.9 ± 5.8 to 12.9 ± 4.2). Additionally, the percentage of the global longitudinal strain of the left ventricle was notably reduced (P = 0.042), and the left-ventricular ejection fraction showed a trend of improvement (53.2 ± 5.9% to 56.3 ± 4.7%) [30].

Expert Opinion

Cardiovascular remodeling in hypertensive patients is more common in patients with left ventricular hypertrophy. HFpEF is a long-term complication in patients with hypertension, and the progression to clinical HFpEF is rapid in patients with uncontrolled hypertension. The reduction of NTProBNP is an established effect of sacubitril/valsartan treatment. The change in left ventricle end-systolic and end-diastolic volumes, left atrial mass index, and diastolic parameters on the tissue Doppler studies even before any demonstrable change in LVEF with sacubitril/valsartan treatment is a marker of improved cardiac remodeling parameters.

Sacubitril/valsartan not only provides superior 24-h blood pressure control, particularly during the night, but also offers significant benefits in reducing cardiovascular remodeling and managing salt-sensitive and nocturnal hypertension. These advantages make it a valuable option, especially in cases of resistant hypertension where traditional ARB monotherapy may be insufficient. The link between uncontrolled blood pressure and adverse cardiovascular events, including stroke, is well established. In difficult-to-control hypertension or when using traditional combination therapies, such as spironolactone or beta-blockers, achieving optimal blood pressure control often remains challenging in real-world practice. Sacubitril/valsartan has the potential to address this limitation. Notably, its initial clinical development focused on hypertension before its efficacy in heart failure was investigated and proven. (Fig. 1).

Fig. 1

Benefits of sacubitril/valsartan in hypertension. BP blood pressure, DBP diastolic blood pressure, LV left ventricular, msDBP mean seated diastolic blood pressure, msSBP mean seated systolic blood pressure, p probability, SBP systolic blood pressure

Q. Should sacubitril/valsartan be recommended in hypertensive patients with CKD?

Clinical Evidence

A substantial proportion of patients with heart failure and kidney disease have poorly controlled BP. In a real-world analysis, the use of ARNI significantly reduced BP as compared to the ACEI/ARB group overall and across the estimated glomerular filtration rate (eGFR) spectrum, including in advanced CKD. The mean baseline eGFR was 63.8, and 10% had stage 4 or 5 CKD. Patients in the ARNI group experienced more significant SBP reduction at month 3 (− 5.2 mmHg vs. − 2.2 mmHg, ARNI vs. ACEI/ARB; P < 0.001) and month 6 (− 4.7 mmHg vs. − 1.9 mmHg, ARNI vs. ACEI/ARB; P < 0.001). These differences in SBP by 6 months did not vary by eGFR above and below 60 ml/min/1.73 m2 continuously across a wide range of eGFR (Pinteraction > 0.10 for both) [31]. In the PARAMOUNT trial involving patients with HFpEF, treatment with sacubitril/valsartan was administered for 36 weeks. The treatment resulted in lower serum creatinine levels and a higher eGFR compared to valsartan. The mean serum creatinine increase was 0.03 mg/dl in the sacubitril/valsartan group and 0.09 mg/dl in the valsartan group (P = 0.007). Accordingly, the decline in eGFR was lower in the sacubitril/valsartan group than in the valsartan group (− 1.5 vs. − 5.2 ml/min per 1.73 m2; P = 0.002). Moreover, in a recent meta-analysis, both omapatrilat and sacubitril/valsartan demonstrated a favorable effect on renal function compared with ACE inhibitors or ARB monotherapy in patients with heart failure. It remains to be seen whether a similar nephroprotective effect of sacubitril/valsartan can be found in patients with hypertension. A total of 15 adverse events were associated with the high-level group term "renal disorders". These occurred in three patients in the sacubitril/valsartan group (2.0%) and nine patients in the valsartan group (5.9%) [32].

Expert Opinion

Sacubitril/valsartan can be an essential add-on therapy in patients with CKD where BP control is challenging to achieve with the limitations of existent treatments. Although sacubitril/valsartan has greater potential to reduce blood pressure, regardless of underlying kidney function, its safe use in stable CKD patients and those on maintenance hemodialysis cannot be recommended dogmatically, as more evidence is needed. Caution, however, will have to be exercised for monitoring potassium with due consideration for electrolyte imbalance inherent with both CKD and the medicines used. Approval by local authorities regarding the e-GFR threshold for initiating and continuing sacubitril/valsartan should be kept in mind. The sacubitril/valsartan can play a vital role in managing the associated resistant HTN in a patient with CKD who does not tend to retain potassium. ARNI has been a drug under evaluation for resistant HTN beyond its use in HF. As CKD is an important contributor to the cause of resistant HTN, it is unclear whether its propensity to retain potassium is significant enough to avoid its use in CKD patients, and more data are needed.

Safety and Tolerability

Q. Is there any AE reported for ARNI that led to discontinuation of therapy?

Clinical Evidence

The PARAMETER study found that sacubitril/valsartan was more effective than olmesartan in lowering clinical and ambulatory central aortic and brachial BP in elderly patients with systolic hypertension and stiff arteries, as has been demonstrated for the first time. The incidence of AEs was slightly higher in the sacubitril/valsartan group (57.6%) versus the olmesartan-based regimen (53.8%). Nasopharyngitis was the most observed AE. The overall incidence of serious AEs was low and similar between the sacubitril/valsartan (7%) and olmesartan-based groups (5.8%). The incidence of AEs, serious AEs, and drug-related AEs leading to discontinuation of the study were similar in both treatment groups. During the 48th week of the study, a single patient from the sacubitril/valsartan group experienced mild angioedema. This situation did not necessitate stopping the medication or hospitalizing the individual to the hospital, and it was fully resolved by the end of the study. In the group that received olmesartan, two fatalities were recorded – one due to cardiorespiratory arrest and the other due to respiratory failure. On the other hand, one case of myocardial infarction fatality was reported in the group that received sacubitril/valsartan [26].

The post hoc analysis by Kario et al. concludes the potent 24-h BP-lowering effect of sacubitril/valsartan, highlighting its efficacy in the non-dipper profile of nocturnal BP. Both sacubitril/valsartan and olmesartan were well tolerated. There were no significant differences between groups related to the reported AEs. The most frequently observed AE was nasopharyngitis. In the groups that received sacubitril/valsartan 200 and 400 mg, one (0.8%) and two (1.4%) patients versus two (1.4%) patients on olmesartan 20 mg/day discontinued the study due to drug-related AEs [25].

Expert Opinion

The incidence of hyperkalemia is significantly higher in patients with an eGFR of less than 60 ml/kg/min than in those with no underlying kidney disease. Although this ADR is much more severe with concurrent use of MRA, it is not certain at this point whether sacubitril/valsartan can be safely used without frequent monitoring for RFT and electrolytes. The anti-hypertensive drug sacubitril/valsartan will not have any different adverse effects than observed in therapy for heart failure. Once-a-day doses, precisely both 100- and 200-mg doses, may be well tolerated.

Care should be taken when using sacubitril/valsartan in conjunction with other medications. For example, sacubitril/valsartan should not be used with ACEIs, and there must be a 36-h gap between stopping ACEIs and starting sacubitril/valsartan to prevent a high risk of angioedema, as evidenced by studies with similar drugs [33, 34]. Individuals with a history of angioedema are advised against using sacubitril/valsartan, as they may have an increased likelihood of experiencing the condition. Furthermore, sacubitril/valsartan should not be combined with aliskiren. The simultaneous use of sacubitril/valsartan with medications such as spironolactone, amiloride, or potassium salts can increase the risk of hyperkalemia. Sacubitril/valsartan can be used with other antihypertensive drugs, including loop diuretics, thiazide and thiazide-like diuretics, and beta-blockers, while monitoring hemodynamic parameters. However, sacubitril/valsartan should not be administered with another ARB or renin inhibitor due to the risks of renal impairment and hyperkalemia.