A Meta-Analysis on the Effect and Safety of LCZ696 in the Treatment of Hypertension

Objectives To systematically evaluate the differences in effect and safety of LCZ696 and angiotensin receptor blockers (ARBs) in the treatment of hypertension. Methods We searched PubMed, Cochrane, Web of Science, and Ovid, collected randomized controlled trials (RCTs) about the effect and safety of LCZ696 and ARBs in hypertensive patients, extracted relevant data and evaluated the quality of the included literature according to the RCT quality evaluation standard recommended by Cochrane Reviewer's Handbook, using RevMan 5.3, and performed meta-analysis. Results Eight RCTs studies were included, with a total of 4313 patients. Compared with ARBs, LCZ696 can better reduce systolic blood pressure (msSBP) (WMD −4.29 mmHg; 95% CI: −5.37 to −3.21; P < 0.001), diastolic blood pressure (msDBP) (WMD −1.87 mmHg; 95% CI:−2.38 to −1.36; P < 0.01), ambulatory systolic blood pressure (maSBP) (WMD −3.37 mmHg; 95% CI:−4.26 to −2.47; P < 0.01), and ambulatory diastolic blood pressure (maDBP) (WMD −1.47 mmHg; 95% CI: −1.97 to −0.97; P < 0.01). In terms of safety, LCZ696 is basically the same as ARBs, but LCZ696 is more likely to cause cough than ARBs (OR = 2.38; 95% CI: 1.27 to 4.47; P < 0.01). Conclusion LCZ696 can significantly reduce the blood pressure level of patients with hypertension, but it is necessary to pay attention to whether the patient will experience coughing after taking the drug.


Introduction
Hypertension is a chronic condition that contributes to worldwide morbidity and mortality more than any other risk factor. As reported, the number of patients with hypertension was estimated to be 31.1% among adults in 2010 [1]. Hypertension is the most common cardiovascular leading risk factor and underlies heart failure (HF), coronary artery disease, stroke, and chronic kidney disease. Hypertensive heart disease includes the development of diastolic dysfunction, left ventricular hypertrophy, and HF with preserved and reduced ejection fraction [2]. erefore, the optimal treatment of hypertension can prevent the development of HF.
Blood pressure can be controlled by changing diet and lifestyle, but drug treatment is used when these methods are not effective. Commonly prescribed antihypertensive drugs include thiazide-diuretics, β-blockers, calcium channel blockers, angiotensin converting enzyme (ACE) inhibitors, and angiotensin II receptor blockers (ARB) [3]. However, lots of treated patients still cannot effectively control blood pressure level, and we need to keep looking for better antihypertensive agents to achieve BP goals and reduce cardiovascular events.
Various studies have revealed the potential of LCZ696 as an antihypertensive drug [4][5][6]. LCZ696 provides highly selective inhibition of neprilysin and blockade of the angiotensin receptor. It plays an important role in improving HF, reducing ejection fraction, and controlling blood pressure [7,8]. Here, we searched studies and performed a meta-analysis on available randomized clinical (RCT) trials to research the effect and safety of LCZ696 in hypertension patients.

Methods
Our search strategy is illustrated in the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) [9] reporting guideline flowchart in Figure 1.

Inclusion Criteria.
Studies meeting the following criteria were selected: (1) e trial was a RCT with complete data (2) Patients with clinical diagnosis of hypertension (3) LCZ696 was used in the experimental group (any dose) (4) ARBs were used in the control group (5) ere were adverse events (AEs) in the outcome indicators

Exclusion Criteria.
Studies that used only self-report or informant report as an outcome were excluded. We excluded animal experimental studies as well as case reports from the meta-analysis. In the same way, all studies that are not written in English, non-RCT studies, duplicate studies, single-arm studies, review articles, and conference articles were eliminated.

Extraction of Data.
Study data were extracted by two of the authors. Studies that clearly did not meet the inclusion criteria were excluded by reading the title and abstract. After reading the full text, they decided whether to include these studies which may meet the inclusion criteria. If there was a problem of disagreement between the two authors, it was resolved through negotiation or decided after discussion with the third researcher.

Study
Quality. e risk of bias of RCTs was assessed using the Cochrane Collaboration's tool from 7 aspects: (1) Random sequence generation (selection bias) (2) Allocation concealment (selection bias) (3) Blinding of participants and personnel (performance bias) (4) Blinding of outcome assessment (detection bias) (5) Incomplete outcome data (attrition bias) (6) Selective reporting (reporting bias) (7) Other bias 2.6. Outcome Indicators. In eligible articles, the main indicators extracted were the mean reductions in systolic blood pressure and diastolic blood pressure in the sitting position (msSBP, msDBP), the mean reductions in 24-hour ambulatory SBP (maSBP) and 24-hour ambulatory DBP (maDBP), and the number of participants who achieved BP, msSBP, and msDBP control. e safety outcome was any AEs occurring during the follow-up point.

Statistical Analysis.
is meta-analysis was performed using the statistical software RevMan 5.3. For the continuous variables, such as msSBP, msDBP, maSBP, and maDBP, the data was represented as the weighted mean difference (WMD) between the experimental group and the control group, with a 95% confidence interval (CI), and we performed subgroup analysis to evaluate the effect about BP control based on different doses of LCZ696. For binary variables, such as AEs, the effect size was represented as an odds ratio (OR) with a 95% CI. e chi-square test was used to assess heterogeneity between studies. When P > 0.1 or I 2 <50%, the fixed-effect model was applied; otherwise, the random-effect model was used for data analysis.

Publication Bias.
Funnel plots and Egger test were used to assess potential publication bias. When two-sided P value < 0.05, it means there was publication bias.
2.9. Sensitivity Analysis. We conducted sensitivity analysis. In the RevMan5.3 software, the included studies were removed one by one, and the stability of the results was evaluated by analyzing the changes in the pooled WMD and the pooled OR.
ere were 4313 patients, 1917 patients were randomly assigned to the ARBs group, and 2396 patients were randomly assigned to the LCZ696 group.
Studies population included untreated patients (newly diagnosed patients or those who had not been taking any antihypertensive drug for ≥4 weeks before screening) or treated with antihypertensive drugs for ≥4 weeks before screening, and mean sitting systolic BP (SBP) ≥140 to <180 mm Hg at screening (for untreated patients only) or ≥120 to ≤160 mm Hg at screening and ≤180 mm Hg at the end of the washout period (for treated patients only). e treatment period ranged from 4 weeks to 52 weeks. Some basic characteristics of the included studies are collected in Table 1.

Study Quality.
Quality of studies was assessed by the Cochrane Collaboration's Risk of Bias tool and all included have acceptable quality. All trials were multicenter, randomized, double-blind, active-controlled, parallel-group studies. e included studies were all high-quality articles (level A). Detailed information on the risk of bias is shown in Figure 2.

AEs.
All included studies had reported several drug-related adverse events after treatment with LCZ696 or ARBs [10][11][12][13][14][15][16][17]. A pooled analysis of all adverse events data showed that there were statistical differences between LCZ696 and ARBs groups in adverse events (OR � 1.13; 95% CI:1.02 to 1.24; P < 0.05; I 2 � 0). e results were more favorable to the ARBs group. More exactly, in all the included studies, LCZ696 could increase the incidence of cough in patients (OR � 1.71; 95% CI: 1.33 to 2.18; P < 0.001; I 2 � 0). But except for cough, the results of every adverse event that occurred showed no statistical difference between the LCZ696 and ARBs groups. e detailed analysis of the data is shown in Table 2.

Publication Bias Review.
is meta-analysis only included 8 studies. According to the requirements of the Cochrane Reviewer's Handbook, the funnel chart generally requires more than 10 studies to be meaningful; otherwise, its test power will decrease, and the evaluation of publication bias is not accurate, so publication bias evaluation was not performed. 3.6. Sensitivity. Among the 8 studies included in this metaanalysis, different types of studies were eliminated in turn through the analysis of the study characteristics and the differences in patient baseline characteristics; the remaining studies were combined with statistics (pooled WMD or pooled OR) to perform the meta-analysis again. ere was no difference between the merged result and the original result.

Discussion
LCZ696 combines the actions of an ARB and valsartan with a neprilysin inhibitor sacubitril [7]. It is the first new drug known as a dual inhibitory effect. e main factors and pathogenesis of hypertension are generally believed to be due to the fluid retention and reninangiotensin-aldosterone system (RAAS) excessive activation. Other studies also had shown that the excessive activation of the sympathetic nervous system (SNS) promotes the reabsorption of the kidneys and damages the pressure natriuretic effect, thereby inducing hypertension [18]. e activation of the RAAS system is caused by many reasons. Angiotensin II promotes smooth muscle contraction, increases ventricular cell synthesis, aldosterone secretion, and arterial smooth muscle cell growth, and can also increase blood pressure. Valsartan inhibits the abnormal activation of the RAAS system by inhibiting angiotensin II receptors, thereby reducing peripheral vascular resistance and reducing fluid retention by inhibiting vasoconstriction and aldosterone secretion. Neprilysin is a neutral endopeptidase that degrades several potentially beneficial vasoactive peptides, including natriuretic peptides, bradykinin, and adrenomedullin, and sacubitril can enhance the effects of these peptides by inhibiting neprilysin, thus promoting vasodilation and increasing urine volume [10]. erefore, we believe that neprilysin inhibition simultaneously with angiotensin receptor blockade had the potential to counteract some of the mechanisms contributing to arterial stiffening in patients with systolic hypertension and could lower central aortic pressure more effectively than an ARB alone. An experiment called PARADIGM HF studied by JV McMurray et al. included 8442 patients with HF (NYHA II-IV, LVEF≤40%, 88% ejection fraction less than 35%). e therapeutic effect of enalapril on patients with HF was compared with LCZ696. e results showed that LCZ696 can significantly reduce the cardiovascular mortality and HF-related hospitalization rates in patients, and it is better than enalapril in clinical symptoms and long-term prognosis for patients with HF [19]. In addition, LCZ696 can prevent cardiovascular disease and renal insufficiency and has antichronic kidney disease (CKD) and anticardiovascular disease (CVD) effects [20,21]. For patients with severe HF, it is necessary to distinguish between advanced HF (AdHF) and end-stage HF. AdHF patients have intolerance to drugs acting on the renal axis, i.e., ACE-I, ARB, or LCZ696, due to hypotension and/or worsening renal function, with risk of 20% for mortality in 1 year. But end-stage HF patients have an extremely severe cardiomyocyte dysfunction and irreversible organ dysfunction and do not respond to inotropic  drugs. e presence of the aforementioned features suggests an irreversible condition of end-stage HF, for which drug treatment or advanced therapies, such as ventricular-assist device implantation, are contraindicated and palliative cares should be pursued [22]. Hypertension is a reversible factor of early HF. Longterm hypertension will increase the ejection resistance of the heart and thicken the ventricular wall, which will lead to ventricular remodeling and chronic HF [23]. Hypertension is the most important risk factor for death from cardiovascular and cerebrovascular diseases, bringing a heavy burden of disease to society. In 2017, the number of deaths due to hypertension in China reached 2.54 million, of which about 69% were deaths from stroke, 54% were deaths from ischemic heart disease, 41% were deaths from other cardiovascular diseases, and another 43% were deaths from chronic kidney disease due to high blood pressure [24].
ere are also studies showing that hypertension is a high  risk factor for Alzheimer's disease [25]. As mentioned in Severino P. et al.'s article [26], risk factors, such as hypertension, diabetes, hyperlipidemia, smoking, and inflammation, not only can cause the pathological changes of large blood vessels, but also are pathogenic factors of coronary microvessels. ese risk factors can lead to abnormal microvascular function through endothelial cell-dependent and independent mechanisms and eventually lead to ischemic heart disease and heart failure. LCZ696 can effectively lower blood pressure. erefore, it can improve heart failure caused by microcirculation dysfunction, which is of great significance to patients with abnormal microcirculation function.
e efficacy test results show that LCZ696 has a better antihypertensive effect than the ARB drug valsartan alone [27], mainly because sacubitril and valsartan have a certain synergistic effect; on one hand, it inhibits the RAAS system; on the other hand, it can reduce fluid retention. From the perspective of safety, compared with ARBs, LCZ696 in this study showed no significant difference in safety except for a mild cough (these studies did not report patients who gave up LCZ696 treatment because they could not tolerate cough); that is, compared with ARB drugs alone, LCZ696 has the characteristics of a more significant antihypertensive effect and no obvious safety difference. Based on its remarkable effect and safety, LCZ696 may become one of the Subtotal (95% CI) Heterogeneity: tau 2 = 1.58; chi 2 = 13.70, df = 4 (P = 0.008); I 2 = 71% Test for overall effect: Z = 5.03 (P < 0.00001)

Limitations
First of all, this study strictly followed the inclusion and exclusion criteria and finally only included 8 studies. e number of studies was relatively small, and a larger research sample size is needed to fully reflect the effectiveness and safety of the drug. Secondly, the length of the included studies was inconsistent, and it lacked sufficient basis for the safety evaluation of long-term using LCZ696 in the treatment of hypertension.

Conclusion
Although this meta-analysis only included 8 studies and 4313 patients, the results showed that, compared with ARBs, LCZ696 showed better advantages in lowering blood pressure and can be used as an alternative antihypertensive drug.

Conflicts of Interest
e authors declare that they have no conflicts of interest.