Effect and safety of LCZ696 in the treatment of hypertension: A meta-analysis of 9 RCT studies.

BACKGROUND: LCZ696 has been introduced in patients with hypertension in several trials. Here, we performed a meta-analysis to evaluate the effect and safety of LCZ696 in hypertensive patients.
METHODS: PubMed, Embase, the Cochrane Library and ClinicalTrials.gov databases were searched to identify the available randomized controlled trials (RCTs) investigating the effect and safety of LCZ696 in hypertension patients. The last search date was October 31, 2018.
RESULTS: Nine RCTs with 6765 subjects were finally included, in which 8 trials compared the effect and safety between LCZ696 and angiotensin receptor antagonists (ARBs). Evidences showed LCZ696, compared with ARBs, achieved a better blood pressure control rate (OR 1.24, 95% CI: 1.14-1.35), specifically, LCZ696 were better at reducing systolic blood pressure [WMD -4.11 mmHg, 95% CI: (-5.13, -3.08) mmHg], diastolic blood pressure [WMD -1.79 mmHg, 95% CI: (-2.22, -1.37) mmHg], mean 24-hour ambulatory systolic blood pressure [WMD -3.24 mmHg, 95% CI: (-4.48, -1.99) mmHg] and mean 24-hour ambulatory diastolic blood pressure [WMD -1.25 mmHg, 95% CI: (-1.81, -0.69) mmHg]. There was no difference in the events of adverse events (risk ratio [RR] 1.01, 95% CI: 0.39-1.09), serious adverse events (RR 0.80, 95% CI: 0.52-1.22) and discontinuation of treatment for any adverse events (RR 0.79, 95% CI: 0.56-1.11) between LCZ696 group and ARB/placebo group, except LCZ696 reduced the rate of headaches (RR 0.69, 95% CI: 0.48-0.99) while increased cough (RR 2.12, 95% CI: 1.11-4.04; P = .02; I = 25%).
CONCLUSION: Our finding provides evidence that LCZ 696 was more effective than ARB on blood pressure control and was safe enough in patients with hypertension.

Introduction

Hypertension (HTN) is a leading risk factor for almost all different cardiovascular diseases (such as coronary disease, left ventricular hypertrophy, atrial fibrillation, stroke, and renal failure, etc). The number of patients with elevated blood pressure is huge, as reported, and its estimated prevalence among adults is 31.1% in 2010.[ Furthermore, the number is predicted to increase with the increasing prevalence of obesity and the aging of the population.[

Choosing right drugs is very important for patients with HTN. Currently, thiazide diuretics, calcium channel blockers (CCBs), angiotensin receptor blockers (ARBs), or angiotensin-converting enzyme (ACE) inhibitors have been recommended as the first-line agents for the initiation of pharmacological therapy in HTN patients.[ However, many treated patients still cannot reach the ideal blood pressure level, and we still need to keep looking for better anti-HTN drugs to achieve BP goals and reduce cardiovascular events and other complications.

LCZ696 (Entresto, sacubitril/valsartan) is the first of a new drug class referred to as angiotensin receptor-neprilysin inhibitor (ARNi). Several large clinical trials have confirmed its role in improving heart failure, and also revealed its potential for blood pressure control.[ Here, we queried literature and performed a meta-analysis on available randomized clinical trials (RCTs) to investigate the effect and safety of LCZ696 in HTN patients.

Material and methods

Ethics statement

As all analyses were based on previously published studies, and no ethical approval or patient consent was required.

Search strategy

Our authors searched the following several databases for primary studies: PubMed (http://www.ncbi.nlm.nih.gov/pubmed), Embase (http://www.embase.com), the Cochrane Library (http://www.cochrane.org), and ClinicalTrials.gov databases (http://www.clinicaltrials.gov/) (all up to October 14, 2018). Medical Subject Headings (MeSH) and corresponding keywords including as shown below: “sacubitril/valsartan”, “LCZ696”, “neprilysin inhibitor”, “AHU377”, “entresto”, and “angiotensin receptor neprilysin inhibitor”. Relevant articles’ reference lists were also used to supplement the search entry. No language restrictions were set.

Study selection

Suitable studies were elected if they met the following inclusion criteria:

the trial was a RCT;

the experimental group used LCZ696;

the control group used ARBs or placebo (any dose, type);

investigating the impact of LCZ696 on blood pressure control;

providing data about adverse events.

We excluded some unqualified articles. Two cross-over trials, which has less patients and shorter observation time, were excluded. Conference articles were excluded for avoiding to incorporate repeated publication. Specific details of the study selection for this meta-analysis are shown in Figure 1.

Figure 1

Flow diagram of the study selection process.

Data extraction

A rigorous data collection table was used for data extracting important information. Two investigators (Q. L. and L. L.) independently finished the task of finding reference lists of the eligible articles. Controversial articles were adjudicated by a third author. Among the eligible articles, data extracted including the following information:

first author's name;

publication year;

types of trials design;

numbers of subjects enrolled;

general characteristics of participants, including age, sex, BP, and so on;

names and doses of intervention drugs, and durations of treatment;

change of systolic blood pressure (SBP), diastolic blood pressure (DBP), mean 24-hour ambulatory SBP (maSBP), and mean 24-hour ambulatory DBP (maDBP);

numbers of patients who achieved BP control;

incidence of adverse events (AEs).

Quality assessment

The Jadad scale was used for the quality assessment, which is an established procedure. The scores of the Jadad scale range from 0 to 7 points, and mainly in 4 aspects:

the appropriateness of the randomization methods (1–2 points);

allocation concealment (1–2 points);

double-blind design (1–2 points);

the analysis and reasons for withdrawals and dropouts (0–1 point).

Two reviewers independently assessed the quality of included studies. Fortunately, they had no disagreements. The scores of Jadad scale range from 0 to 7, Studies with the score ≥4 should be considered as having a good quality, while ≤3 as having a poor quality.

Outcome measures

The end points were compared between the LCZ696 group and ARB or placebo group:

changes from the baseline in SBP, DBP, maSBP, and maDBP;

numbers of participants who achieved BP control, defined as SBP/DBP <140/90 mm Hg;

AEs, mentioned by the researchers.

Statistical analysis

This meta-analysis was conducted using statistical software STATA version 12.0. For continuous variable, data were represented as the weighted mean difference (WMD) with a 95% confidence interval (CI) between the intervention and control groups. We performed subgroup analysis to assess the effect on BP control based on the dose of LCZ696. For dichotomous outcome data, the risk ratio (RR) with 95% CI was calculated. The Heterogeneity between studies was assessed using the chi-squared test (presented as I), the random effects model (which using the D-L method) was applied when I ≥50%, otherwise the fixed effects model (which using the Mantel-Haenszel method) was used for data analysis.[ And z test used for overall effect. Statistical significance was set at 0.05.

Publication bias

Funnel plots and Begg test were used to probe for publication bias. Two-sided P value <.05 was regarded as statistically significant for all included studies. All statistical analysis was performed using STATA version12.0 and Review Manager 5.3 statistical software for the meta-analysis.

Results

Characteristics of enrolled studies

A total of 1451 relevant studies had been found from the above-mentioned databases, of which 9 studies (Cheung's study,[ Izzo's study[, Schmieder's study[, Supasyndh's study[, Williams's study[, Nct's study[, Ruilope's study[, Nct 's study[, Kario's study [) with 6765 individuals were finally assessed for eligibility based on the inclusion and exclusion criteria.

A summary of the primary details of these included studies are showed in Figure 1 below. Here, 8 trials touch on a comparison between LCZ696 and ARB groups. All selected studies are clinical RCTs. The mean age ranged from 51.6 to 70.7 years old, and more male than female. The duration over which outcomes were measured ranged from 8 weeks to 52 weeks. The detailed characteristics of these studies are listed in Table 1.

Table 1

Baseline Characteristics of Trials included in the Meta-Analysis.

Studies were quantitatively classified according to the Jadad scale respectively. All trials included are judged as high-quality articles (Jadad score ≥3), and they are randomized, double-blind, parallel-group, placebo and/or active-controlled, multicenter studies. The details of the risk-of-bias analysis are shown in Table 2.

Table 2

Quality evaluation of clinical trials inclued using the Jadad scale.

Assessment of blood pressure control

As outlined in the following figures (), we identified 8 RCTs (Cheung's study[, Izzo's study[, Schmieder's study[, Supasyndh's study[, Williams's study[, Nct's study[, Ruilope's study[, Nct 's study[) which enrolled in 5401 patients for the effect of LCZ696 on BP reduction compared with ARB groups.

Comparison of LCZ696 with ARB groups on the outcome of systolic blood pressure. ARB = angiotensin receptor antagonist.

Comparison of LCZ696 with ARB groups on the outcome of diastolic blood pressure. ARB = angiotensin receptor antagonist.

Comparison of LCZ696 with ARB groups on the outcome of mean 24-hour ambulatory SBP. ARB = angiotensin receptor antagonist, SBP = systolic blood pressure.

Comparison of LCZ696 with ARB groups on the outcome of mean 24-hour ambulatory DBP. ARB = angiotensin receptor antagonist, DBP = diastolic blood pressure.

Comparison of LCZ696 with ARB on the blood pressure control rate. ARB = angiotensin receptor antagonist.

LCZ696 significantly lowered SBP (WMD −4.11 mmHg;95% CI, −5.13 to −3.08; P <.001; I = 99.9%), DBP (WMD, −1.79mmHg; 95% CI, −2.22 to −1.37; P <.001; I = 99.7%), maSBP (WMD, −3.24mmHg; 95% CI, −4.48 to −1.99; P <. 001; I = 99.9%), maDBP (WMD, −1.25mmHg; 95% CI, −1.81 to −0.69; P <.001; I = 99.8%) in comparing with ARB. People with LCZ696 treatment more easily achieved a successful BP control (OR = 1.24; 95% CI, 1.14 to 1.35; P <.001; I = 35.7%) than ARB treatment.

LCZ696 treatment with 100 mg daily showed a more obvious reduction in SBP (WMD, −1.58 mmHg; 95% CI, −2.09 to −1.07; P <. 001; I = 92.2%), DBP (WMD, −0.66mmHg; 95% CI, −0.98 to −0.33; P <.001; I = 92.7%), maSBP (WMD, −0.51mmHg; 95% CI, −0.9 to −0.12; P = .01; I <0.001%), maDBP (WMD, 0.76mmHg; 95% CI, 0.49 to 1.03; P <.001; I <0.001%) in comparing with ARB groups. And LCZ696 treatment showed an advantage in successfully achieving BP control (OR, 1.15; 95% CI, 0.96–1.38; P = .131; I =0%).

LCZ696 at 200 mg/d displayed a further reduction in SBP (WMD, −4.17 mmHg; 95% CI, −5.54 to −2.81; P <.001; I = 99.8%), DBP (WMD, −2.02 mmHg; 95% CI, −2.51 to −1.52; P <. 001; I = 99.6%), maSBP (WMD, −2.97 mmHg; 95% CI, −4.64 to −1.31; P <. 001; I = 99.9%), maDBP (WMD, -1.37 mmHg; 95% CI, -2.09 to −0.64; P <.0001; I = 99.8%) in comparing with ARB. The data proved that advantage of LCZ696 treatment in achieving BP control successfully (OR, 1.25; 95% CI, 1.05 to 1.48; P = .011; I = 60.6%) than ARB treatment.

LCZ696 at 400 mg/d also displayed a more obvious reduction in SBP (WMD, −5.04 mmHg;95% CI, −6.93 to −3.16; P <.001; I = 99.9%), DBP (WMD, −1.98 mmHg; 95% CI, −2.56 to −1.41; P <.001; I = 99.5%), maSBP (WMD, −4.31 mmHg; 95% CI, −6.55 to −2.06; P <.001; I = 99.9%), maDBP (WMD, −1.56 mmHg; 95% CI, −2.65 to −0.48; P = .005; I = 99.8%). Besides, LCZ696 treatment more easily achieved a better BP control (OR, 1.28; 95% CI, 1.13–1.46; P <.001; I = 38.5%) than ARB treatment.

Adverse events

Systematic evaluations of AEs data analysis were shown in the Table 3. In 9 trials enrolled, the result showed no statistical difference found between LCZ696 and ARB/placebo group in any adverse events (RR= 1.01; 95% CI: 0.39–1.09; P = .83; I = 38%), serious adverse events (RR= 0.80; 95% CI: 0.52–1.22; P = .30; I = 45%) and discontinued because of adverse events (RR= 0.79; 95% CI: 0.56–1.11; P = .18;I = 20%).And the results also demonstrated that adverse events such as dizziness, diarrhea, upper respiratory tract infection, nasopharyngitis, back pain, arthralgia, atrial fibrillation, edema had the same incidence in LCZ696 group and ARB/placebo groups. It is worth noting that LCZ696 treatment could decreased the incidence rate of headache (RR= 0.69; 95% CI: 0.48–0.99; P = .004; I =0%) while increase cough (RR= 2.12; 95% CI: 1.11–4.04; P = .02; I =25%).

Table 3

Adverse events reported in the included studies.

Assessment of publication bias

Sensitivity analysis was conducted to evaluate the effect of studies with a high risk of bias on overall effect size. Among these RCTs, no evidence of publication bias was detected (see S1and S2, Supplemental Content, which demonstrates the result of publication bias).

Discussion

Main findings

In the present study, we systematically analyse the current available studies that investigate the effects and safety of LCZ696 on blood pressure control. These findings from the current study demonstrated that LCZ696, comparing with ARBs, can lower effectively BP (including SBP, DBP, maSBP, maDBP), and elevate the numbers of participants who achieved BP control. And the subgroup analysis clearly showed that LCZ696's intensity of BP-lowering is in relation to the dose of drug. In addition, LCZ696 group had no more adverse events occurrence comparing with ARB/ placebo groups among the eligible trials. LCZ696 treatment effectively reduced the rate of headache comparing with ARB/ placebo groups however increased cough. In brief, as a drug combining of with ARB and neprilysin inhibitor, LCZ696 exhibited its superiority.

A study in reducing blood pressure revealed that in patients with uncontrolled hypertension, fixed-dose combinations may help to improve adherence and persistence, which were crucial for the success of medical treatment.[ Besides, the combination therapy is superior to a doubling of monotherapy by 4 to 5 times.[

LCZ696 is an angiotensin receptor-neprilysin inhibitor, literally, LCZ696 consists of valsartan and sacubitril in a salt delivering a 1:1 molar ratio of its constituents after oral administration.[ Valsartan, one of Angiotensin II receptor blockers, selectively blocks AT 1 and inhibits angiotensin-II-dependent aldosterone release. By inhibiting renin-angiotensin-aldosterone system which plays a big role in the pathogenesis of HTN, ARBs are regarded as potent, effective and largely safe drugs for the management of hypertension. Sacubitril is a prodrug that can be hydrolyzed to form LBQ657, which also potently inhibit neprilysin (NEP).[The NEP is known as a key enzyme in the degradation of natriuretic peptides, and direct consequence of NEP inhibition is circulating natriuretic peptides (NPs) and other vasoactive peptides increase. The synergistic effect of sacubitril and valsartan is systemic vasodilation, meanwhile diuresis and natriuresis increase, which decreases in peripheral vascular resistance and plasma volume contraction, all important actions for the lowering of BP.[

Findings in relation to other studies

Searched in databases mentioned, we found several meta-analyses concerning the LCZ696. Our results are consistent with Zhao’ conclusion[ that LCZ696 effectively reduce BP and patients with LCZ696 treatment could more easily achieve the BP goals, although inclusion and exclusion criteria differ: we excluded conference articles and cross-over trials as mentioned before. Li et al[ conducted a meta-analysis about the safety of LCZ 696, and they got a conclusion that LCZ696 significantly increased the risk of angioedema and dizziness. After expanding the sample size, we got different conclusions that LCZ696 significantly reduced incidence of headache, while not affect edema.

Implications for clinical practice and further research

Studies confirmed the efficacy of sacubitril/valsartan on improving heart failure. McMurray et al performed a big study named PARADIGM-HF study, which enrolled 8442 patients with reduced ejection fraction (EF ≤40%) to compare the effects of LCZ696 monotherapy with enalapril, they terminated the experiment in advance with finding that LCZ696 was superior to enalapril in significantly improving heart function, and could reduce death from cardiovascular causes or hospitalization for HF.[ Besides treatment with LCZ696 don’t influence renal function, even can do better for it.[ Currently, LCZ696 combination has been approved in multiple countries.

Given its ideal validity and reliable safety, LCZ696 may be another first-line medication for patients with hypertension. But still, need enough experimental research to prove its feasibility. Subsequent trials should investigate issues such as characteristics of applicable people, fluctuation of blood pressure, cardiovascular events, and observation of long-term adverse reactions.

Strengths and limitations

The strength of our work lies in the comprehensive literature search, rigorous inclusion and exclusion criteria, careful screening process and enlarged sample size. In our study, we affirmed the advantage of LCZ696 on BP control. However, several possible limitations should be noted. First, 8 trials included had an unclear risk of bias with lacking adequate methodological information such as sequence generation and allocation concealment. Second, except for Schmieder's study[ (52 weeks), Williams's study[ (52 weeks), the other trials had short period of experimental observation, so the results on the adverse effects only reflected the short-term effects of LCZ696 treatment. As for long-term adverse reactions, more efforts should be made.

Conclusion

Overall, the meta-analyses illustrated that LCZ696 was more effective than ARB on blood control and as safe as ARB/placebo in patients with hypertension.

Author contributions

Data curation: Qiongqiong Li, Lina Li.

Formal analysis: Fuzhen Wang, Youxia Liu.

Methodology: Wei Zhang, Youxia Liu.

Software: Fanghao Wang, Yipeng Guo.

Supervision: Junya Jia, Shan Lin.

Writing – original draft: Qiongqiong Li, Lina Li.

Writing – review & editing: Junya Jia, Shan Lin.