Sensitivity analysis was performed for the results with high heterogeneity and different cut-points to assess the robustness of the findings. After the outlier studies were removed, the remaining studies were analyzed again with the pooled MD or RR, and it was observed that the results were robust and not different from the original findings. No significant publication bias was detected for the trials investigating the pooled effect of Sac/Val on nighttime maSBP and maDBP (p = 0.38, p = 0.57), daytime maSBP and maDBP (p = 0.34, p = 0.15), 24-h maSBP and maDBP (p = 0.91, p = 0.15), maPP (p = 0.35), msSBP and msDBP (p = 0.19, p = 0.44), AEs (p = 0.98) and SAEs (p = 0.27) evaluated by Egger's test. The funnel plots are displayed in (Supplementary Fig. S8).

Several previous studies had been conducted to investigate the effect of Sac/Val in the treatment of hypertension; however, evaluation on the effect of out-of-office BP which are more sensitive prognostic factors of HMOD, is still lacking [19,20,21]. This is the first systematic review and meta-analysis which investigated the effect of Sac/Val, focusing on both office BP and out-of-office BP monitoring, which will be beneficial for future clinical practice. Our findings indicated that a combined single-pill Sac/Val was associated with an advantageous decrease in nighttime, daytime, 24-h mean ambulatory BP, ambulatory PP and office BP. Moreover, the proportion of patients who achieved a BP control rate was greater in the Sac/Val groups than the comparator groups. The occurrence of AEs and SAEs was comparable between groups; however, 400 mg of Sac/Val induced more coughing than the comparator treatments.

ARNI is a single-pill agent combining valsartan and sacubitril (neprilysin inhibitor). Neprilysin inhibitor, sacubitril, is a prodrug that prohibits and slows down the breakdown of natriuretic peptides (NPs), bradykinin, and other peptides. Consequently, the high circulating NPs induce cyclic guanosine monophosphate generation, thereby producing diuresis, natriuresis, myocardial relaxation and anti-remodeling [41]. NPs also regulate the circadian rhythm of BP, with their levels typically lower at night, which might lead to a sleep time BP increase [42]. These peptides also suppress aldosterone secretion and sympathetic nervous system activity and promote renal protection [14]. The selective blockade of angiotensin receptor-1 by valsartan inhibits sodium and water retention, vasoconstriction, and myocardial hypertrophy [43]. These cardio-related multipotent mechanisms of Sac/Val have the potential to contribute greater therapeutic effectiveness in monitoring of office and out-of-office BP than other standard antihypertensive agents.

Office BP control is the foundational strategy of hypertension monitoring; however, out-of-office BP (ambulatory BP) monitoring has been efficient for more precise prognostic enlightenment of CV events and HMOD [2, 44]. Moreover, it is able to identify white-coat and masked hypertension [2]. Several studies have reported that abnormal nocturnal BP variation is associated with target organ damage and adverse CV outcomes [45, 46]. According to the sleep time BP dipping profile, patients are classified as dippers and non-dippers if their nighttime BP falls by >10% and <10% of the daytime ambulatory BP, respectively. Not only is the non-dipping profile common in hypertensive patients, but it is also related to a higher risk of CV mortality [44]. It had been found that a nocturnal BP reduction >10% of daytime values could retard or prohibit the progress of left ventricular hypertrophy (LVH) [47]. A systematic review on predicted role of nocturnal BP by Hansen TW et al. revealed that a 10-mmHg increase in systolic nighttime BP was associated with hazard ratios 1.16 and 1.14 for total mortality, 1.19 and 1.15 for CV events in hypertensive patients and randomly selected populations in Europe, Asia and South America, respectively (p < 0.001) [48]. Hypertension generally coexists with comorbidities such as diabetes, hyperlipidemia and nighttime BP elevation is frequently observed in these patients [49]. The elevation of ambulatory PP with age is also a representative marker of arterial stiffness and may also be considered as a more accurate measurement than usual office PP [15, 50]. In this meta-analysis, the pooled results showed that Sac/Val effectively reduced ambulatory BP (nighttime, 24-h, daytime) and ambulatory PP compared to ARBs.

Regarding the cardiovascular remodeling which might be progressed in patients with hypertension, Schmieder's 52-weeks study and Chen et al.'s 24-weeks study found that Sac/Val was associated with a greater reduction in left ventricular (LV) mass, which was an independent prognostic factor of CV events [29, 34]. Daubert et al. found that NT-proBNP lowering to <1000 pg/ml was associated with a reverse cardiac remodeling in HFrEF patients [51]. Hussain et al. also found that stage 1 hypertensive patients with a raised NT-proBNP experienced more CV risk compared to those with hypertension stage 2 and a lower NT-proBNP [52]. In hypertensive patients, Wand TD et al.'s study found that Sac/Val provided the greater reduction of NT-proBNP than the Olmesartan group at week 12 [17]. Likewise, two before and after studies also confirmed that Sac/Val caused a significant decrease of NT-proBNP level from baseline (p = 0.037 and p < 0.001), respectively in hypertensive patients [53, 54].

Hypertension prevalence increases in older patients, and most of them have other comorbidities such as postural hypotension, chronic kidney disease (CKD), diabetes, and other CV problems; therefore, pharmacological treatment has been complex and has become a challenging [2]. However, BP increase is an important risk factor to manage, and a cohort study by Corrao et al. has shown that better antihypertensive treatment compliance is related to a reduction in CV mortality and morbidity, even in very old patients [55]. According to this meta-analysis finding, it was observed that Sac/Val reduced both SBP and DBP significantly in both elderly and non- elderly patients (p < 0.001) compared to ARBs alone. On the other hand, some multicenter retrospective studies based on age (≥65 years vs <65 years) in patients with hypertension and HF indicated that the elderly group had a greater incidence of hypotension with the Sac/Val treatment suggesting it may need for careful dose adjustment and close monitoring of laboratory parameters in this population [56, 57].

The previous studies found that the proportion of BP control rate <140/90 mmHg achievement during antihypertensive treatment was low in Asian population compared to Canada, US and Europe population. The high salt intake, smoking, sedentary lifestyles and obesity are the common risk factors for hypertension in Asian population [3]. Therefore, it was found that for Asian patients, sodium excretion antihypertensive agents become a beneficial option. ARNI has been currently approved as an antihypertensive agent in China, and Japan [5]. The studies included in this systematic review were mostly conducted in Asian patients. Our findings of analysis with only Asian patients indicated that both 200 mg and 400 mg of Sac/Val showed a significant reduction in both office and ambulatory BP (p < 0.001) compared to ARBs alone. However, there may be barriers like the cost of this drug and its handiness for common use [5].

This study included participants with essential hypertension, as well as those with common comorbidities such as heart failure, diabetes mellitus, obesity, and type B aortic dissection [32, 33, 35, 39]. This reflects the diverse clinical characteristics of the hypertensive population and enhances the generalizability of the findings. Sac/Val has primarily approved for the treatment of HFrEF [16]. Moreover, recent guidelines recommend ARNI therapy for hypertensive patients with HFrEF or heart failure with mildly reduced ejection fraction (HFmrEF) [6]. In obese hypertensive patients, Sac/Val was found to improve insulin sensitivity and enhance lipolysis in abdominal adipose tissue compared to amlodipine [35]. A combined analysis study found that, compared to valsartan, Sac/Val decreased HbA1c and new insulin therapy in patients with HF [58]. Additional study also found that Sac/Val significantly lowered HbA1c from baseline in diabetes patients with hypertension [32].

This study involved patients with mild to moderate essential hypertension, isolated systolic hypertension and resistant hypertension, enhancing the practical relevance for treatment decision making in real clinical settings. A previous post hoc analysis found that compared to valsartan, Sac/Val was associated with a more favorable reduction in SBP in patients with apparent resistant hypertension and mineralocorticoid receptor antagonist (MRA)-resistant hypertension [59]. Additionally, two included studies observed that Sac/Val treatment significantly improved the cardiac remodeling and hemodynamic parameters, in addition to lowering BP in resistant hypertension [31, 40]. These findings may contribute to the development of future therapeutic strategies for resistant hypertension.

Regarding adverse events, most of the including studies reported that Sac/Val was well-tolerated and normally safe. It was found that the most frequent trials' reported AEs in Sac/Val group were nasopharyngitis [15, 25, 30]. There was no noteworthy difference in both AEs/SAEs occurrence and discontinuation between Sac/Val and the comparator (ARBs and Amlodipine); however, long-term safety data for Sac/Val could not be established from this meta-analysis. The previous long-term safety study of Sac/Val in hypertension found that most AEs were mild or moderate in intensity [60].

The previous systematic reviews and meta-analyses have shown that Sac/Val can effectively improve sitting BP and 24-h ambulatory BP monitoring compared to ARBs alone, and is generally safe [19,20,21]. Our meta-analysis observation was well aligned with these previous findings and included the most updated evidence. In contrast to previous findings, our meta-analysis additionally focused on nighttime, daytime ambulatory BP and ambulatory PP compared to both ARBs and other antihypertensive agents and performed subgroup analyses in specific patient populations. This systematic review included both RCTs and observational studies, which enhances the applicability of the findings to real-world clinical practice.

This meta-analysis has several strengths, including a well-formed search strategy that covers comprehensive databases and unpublished data or grey literature, the evaluation of sensitivity and subgroup analyses to address heterogeneity and confirm the robustness of the findings, assessment of study quality by using well-established tools. Moreover, this systematic review has been registered in PROSPERO. Nevertheless, several limitations were also noted. First, most included studies had a short follow-up time, indicating that the findings may not provide long-term outcomes. Second, in two included studies, the dosage of the active control, Olmesartan (20 mg/day), was lower than the equivalent dose of Sac/Val (400 mg) [25, 27]. Third, most of the included studies excluded patients with secondary hypertension, indicating that the pooled finding may not be applicable to those patients. Finally, moderate and high heterogeneity were detected in the RCTs and observational studies, respectively. The different control group (Amlodipine) from other studies may be the reason why we found that the Yamamoto K et al. study mostly affects the heterogeneous pooled findings of RCTs [36]. Due to the limited number of retrieved observational articles, we have to pool studies with divergent control groups, study designs, comorbidities, concurrent medications and study settings which could lead to tremendous dissimilarities. However, the sensitivity analyzed findings were still distinctly persistent with the main results.

In conclusion, based on this study, we propose that

These findings may contribute to the development of a modern, promising antihypertensive therapeutic approach that may have cardiovascular and renal-related better profile than the conventional way of therapy for uncontrolled blood pressure patients. Further studies on the long-term effects of ARNI in hypertension, including clinical outcomes and its role in treating resistant hypertension, as well as its impact on diverse populations with common hypertension-related comorbidities, are also warranted to strengthen the findings of the current study.