Efficacy and safety of macitentan for pulmonary hypertension: A meta‐analysis

Abstract Introduction Our purpose of this study is to evaluate the effect and safety of macitentan in the treatment of pulmonary hypertension (PH). Methods We retrieved the safety and efficacy of macitentan treatment for PH using PubMed, the Cochrane Library, EMBASE databases and clinicaltrials.gov. The Cochrane Risk of Bias Tool was used for literature screening and quality assessment. Data analysis was conducted using RevMan 5.4.1 and Stata/SE 15.1 software. Results are presented as standardization mean differences (SMDs) and odds ratio (OR). Results Meta‐analysis of seven randomized controlled trial (RCT) studies and four non‐RCT studies with 2769 patients was included, involving 723 in the macitentan group and 599 in the placebo group. The results of the study showed that macitentan had effectively decreased pulmonary vascular resistance (PVR) (SMD = −0.53, 95% CI: −0.77–−0.29, p < 0.05), cardiac index (CI) (SMD = 0.60, 95% CI: 0.37–0.83, p < 0.05) and N‐terminal pro‐brain natriuretic peptide (NT‐proBNP) (SMD = −0.22, 95% CI: −0.40–−0.03, p < 0.05). Furthermore, macitentan also significantly reduced PVR (SMD = −0.58, 95% CI: −0.80–−0.35, p < 0.05), 6‐min walk distance (6WMD) (SMD = 0.33, 95% CI: 0.15–0.50, p < 0.05), CI (SMD = 0.48, 95% CI: 0.28–0.69, p < 0.05), mean pulmonary arterial pressure (mPAP) (SMD = −0.43, 95% CI: −0.64–−0.23, p < 0.05) and NT‐proBNP (SMD = −0.55, 95% CI: −1.07–−0.03, p < 0.05) between baseline and follow‐up. The adverse reactions to macitentan were mild, with headache, anaemia and bronchitis. Other efficacy and safety outcomes did not reach statistical differences. Conclusion Macitentan therapy for PH is effective and safe. The effectiveness on PVR, mPAP, mean right atrial pressure (mRAP), mortality and other indicators still needs to be further confirmed.


| INTRODUCTION
Pulmonary hypertension (PH) is an uncommon, devastating and progressive disorder, leading to increases in pulmonary vascular remodelling.Right heart failure as an end-stage of PH threatens death. 1 Of all vasodilators, endothelin receptor antagonists, which are strong vasodilators, are capable of stopping the process of cell division, which could remodel pulmonary arterial structural alteration. 2 For more than 30 years, endothelin was first reported as a vasoconstrictor. 3The endothelin receptor antagonist (ERA) receptor subtypes include dual antagonists that block ETA and ETB receptors.The dual ERA bosentan was approved as the first oral therapy for PH. 4,5However, there was an increased incidence of dose-dependent liver transaminase and peripheral edema.Macitentan is the result of this optimization programme, macitentan, an endothelin receptor antagonist of the third generation, has been approved for long-term treatment of PH. 6 Animal experiments showed that treatment with macitentan improved haemodynamic parameters in a monocrotaline model of PH. 7 In an increasing number of clinical studies, marcitentan has shown remarkable efficacy in different types of PH.The SERAPHIN trial was a landmark trial with a large number of enrolled patients and a long observation period, which significantly reduced morbidity and mortality in patients with PH.It has also been shown to improve haemodynamic pulmonary vascular resistance (PVR) and performance in Eisenmenger syndrome-associated pulmonary arterial hypertensions (PAHs), as well as 6-min walk distance (6WMD) and PVR in inoperable chronic thromboembolic PH and left ventricular insufficiency.Meanwhile, the incidence of adverse events such as hepatotoxicity and edema was lower than that of other ERAs.
Nowadays, there is a lack of systematic reviews on macitentan's efficacy and safety in the treatment of PH patients.Thus, a systematic review to determine the efficacy of macitentan in the treatment of PH was necessary.We are searching for relevant literature from the PubMed, EMBASE, Cochrane Library databases and clinicaltrials.gov.

| Data retrieval strategy
The required databases, PubMed, EMBASE and clinical trials, were reviewed and extracted from the literature from the date of establishment to June 2022.Each study was as follows: the first author, year of publication, study population, intervention, race, age, sample size, research technique, main outcome, follow-up time and adverse reactions.The terms included free words and medical subject headings (MeSH) subject words.The English literature can be retrieved with the key words ('pulmonary arterial hypertension' OR 'pulmonary hypertension' OR 'pulmonary artery hypertension' OR 'pulmonary vascular disease' OR 'pulmonary heart disease' OR 'pulmonary cardiac disease' OR PAH) AND (macitentan OR N-(5-(4-bromophenyl)-6-(2-(5-bromopyrimidin-2-yloxy) ethoxy)pyrimidin-4-yl)-N 0 -propylaminosulfonamide OR ACT 064992 OR ACT064992 OR ACT-064992 OR Actelion-1 OR opsumit) AND (clinical trials).In sum, 11 English literature were located.Figure 1 shows the detailed literature screening process.

| Literature screening and data extraction
After the literature was screened from the database, End-Note X9 was used to manage the screened literature, and duplicate studies were excluded using the software.Two researchers then screened the studies separately.In the initial screening, irrelevant articles were excluded according to the standard by reading the titles and abstracts of each article.During the second screening, the full text of the articles was reviewed, and articles for which the outcome data could not be extracted were excluded.After the second screening, the relevant data from the included literature were extracted.Data extracted included the first author, year of publication, study population, race, age, sample size, research method, main outcome, follow-up time and adverse reactions.

| Literature quality assessment
The Cochrane Bias Risk Assessment Table and Newcastle-Ottawa Scale were used by two researchers as bias risk assessment tools in this study to evaluate the quality of the literature.When opinions differ, the decision is reached through discussion or based on the third investigator's intervention.The evaluation indicates that the study by Nobuhiro Tahara, Pankaj Jariwala, Pavel Jansa, Satomi Sakural and Tomas Pulido exhibits highrisk random, allocation and binding biases.Randomized controlled trial (RCT) studies have low-risk random bias, allocation bias, and binding bias.In addition, in all studies, there is an unclear risk of selection bias due to insufficient descriptions of details.

| Analysing the quality of literature
Based on the Cochrane Collaboration methodology, two researchers independently assessed the quality of the literature for bias in meta-analysis, including selection bias and biases in the performance, detection, reporting and analysis of data.Every risk of bias has three levels of uncertainty: low, medium and high.

| Statistical analysis
All analysis data were performed with RevMan version 5.4.1 and Stata/SE 15.1.The study was assessed using a random-effects model, and the included study was assessed as statistically heterogeneous by I 2 with a value exceeding 50%.Otherwise, the fixed-effects model is available.As a result, heterogeneity was considered acceptable.Sensitivity analyses were conducted to assess whether the combined results would be significantly affected by a single study, and funnel plots were used to assess publication bias. 8,9| RESULTS

| Basic information of included literature
The flow chart of the literature search and selection is shown in Figure 1.We retrieved 2769 citations in total.After screening for titles and abstracts, 150 records were excluded because of irrelevance or noncontrolled design.In total, 112 articles remained for further evaluation.Among them, 38 were excluded.Ultimately, we identified seven RCTs, one prospective study, one retrospective study and two cohort studies.

| Search results
Eleven studies completely fulfilled the criteria in the literature, including the studies by Hossein-Ardeschir Ghofrani, 10 Jean-Luc Vachiéry, 11 Michael A. Gatzoulis, 12 Nazzareno Galie 13 and Prof. Olivier Sitbon, 14 and non-RCTs are Nobuhiro Tahara, 15 Pavel Jansa, 16 Nobuhiro Tahara, 17 Satomi Sakurai, 18 Pankaj Jariwala 19 and Tom as Pulido. 20even RCT studies focus on a multicentre, doubleblind, randomized, parallel group, placebo-controlled, Hossein-Ardeschir Ghofrani study.Following the openlabel treatment period, all eligible patients received macitentan 10 mg for 24 weeks.Jean-Luc Vachiéry's study was on left ventricular dysfunction.The macitentan treatment period, therefore, 12 weeks for a follow-up, was the main end of fluid retention or New York Heart Association (NYHA) functional.In Michael A. Gatzoulis's study of Eisenmenger syndrome, clinical assessments and laboratory tests were done at macitentan 10 mg for the double-blind and open-label treatment periods, respectively.Nazzareno Galie's study of PAH was done at week 12.A 28-day screening period was followed by a 1:1:1 randomization in which patients received once daily either macitentan 3 mg, macitentan 10 mg or a placebo.Patients received double-blind treatment until they experienced a primary endpoint event, including a series of haemodynamics, CI, mRAP, mPAP, PVR, SVO2 and N-terminal pro-brain natriuretic peptide (NT-proBNP).In the study of Prof. Olivier Sitbon, in this phase 4 trial, PH was treated with double-blind, placebo-controlled, multicentre treatments over 12 weeks.Satomi Sakurai's study of PH was a prospective, multicentre, open-label, single-arm, phase 3 study with PVR, 6WMD, CI, CO, mRAP, SVO2 and NT-proBNP.Five RCT studies included morbidity and mortality as main ending (Table 1).

| Bias and quality assessment
The results of bias risk evaluation for the enrolled RCTs are shown in Figure 2. Green represents low risk, red represents high risk, and yellow represents unclear risk, and it can be seen that there was no obvious bias in this study.

| Change in PVR: macitentan versus placebo
There was no significant statistical heterogeneity among the results of the studies, and the fixed effects model was used for meta-analysis.There is no significant statistical heterogeneity among the studies, and the fixed-effect model was used (SMD = À0.53,95% CI: À0.77-À0.29,p = 0.000).These differences were statistically significant (Figure 3).
F I G U R E 2 Literature quality assessment.
F I G U R E 3 Meta-analysis of the effects of macitentan versus placebo on pulmonary vascular resistance (PVR).
There was still significant heterogeneity after article by article exclusion indicating that the heterogeneity was stable (Chi 2 = 20.05,p = 0.000, I 2 = 80.1%), and the random effect model was used.These differences were not statistically significant (Figure 7).

| Changes in NT-proBNP: comparison of baseline and follow-up of PH
Patients treated with macitentan significantly improved their NT-proBNP compared with pretreatment baseline measures.Significant statistical heterogeneity was noted among the studies, and the random effect model was used (SMD = À0.55,95% CI: À1.07-À0.03,p = 0.000).These differences were statistically significant (Figure S6).

| Common adverse reactions
Common adverse reactions refer to peripheral edema, headaches, bronchitis and anaemia.Except for peripheral edema (SMD = 1.33, 95% CI: 0.80-2.18,p = 0.27), other symptoms were statistically significant (Figures S10, S11, S12 and S13).outcome is usually right ventricular failure. 21,22Drug therapy for PH consists of the nitric oxide, endothelin and prostacyclin pathways.These specific therapies have improved 5-year survival from 34% in 1991 to more than 60% in 2015. 23ndothelin-1, discovered as endothelial vasoconstrictor peptide as early as 1987, 24 showed potent and long-lasting vasoconstrictor effects on arteries that were never observed with another compound at the time.The ETA receptor is dominant in smooth muscle cells and mediates vasoconstriction and cell hypertrophy, whereas the ETB receptor is expressed mainly on the vascular endothelium and mediates vasodilation.The ETA receptor plays a dominant role in vasoconstriction. 25Macitentan, which was first approved for PAH in 2013, improves its efficacy and tolerability by altering the structure of bosentan, reducing side effects such as hepatotoxicity and lower limb fluid retention. 26,27To our knowledge, the present study is the first, largest and most comprehensive meta-analysis of the efficacy and safety of macitentan in PH patients, summarizing multiple RCT and non-RCT studies.
Seven RCTs included articles reporting numerous adverse reactions during macitentan treatment.This study conducted a meta-analysis of peripheral edema, headache, bronchitis and anaemia.The results showed significant differences between the above adverse reactions and placebo, but the results did not indicate that macitentan treatment increases the incidence of peripheral edema.Headaches, bronchitis and anaemia are the most common adverse reactions, and most patients tolerate them.
Our study has several limitations.Firstly, there are few included literature from RCTs, which may impact the F I G U R E 7 Meta-analysis of the effects of macitentan versus placebo on mean pulmonary arterial pressure (mPAP).
reliability of the results.The results indicate that macitentan treatment affects PVR, CI and NT-proBNP.In the future, even more subjects will enroll in RCT studies to evaluate efficacy and safety.Secondly, the studies included in the meta-analysis were heterogeneous compared with macitentan and placebo.A sensitivity analysis was available.No single study had a significant impact on combining results.So, the results are relatively stable.We could not conduct further subgroup analysis because of the limited data.Finally, the WHO functional class is scarcity.
In conclusion, this meta-analysis showed that macitentan therapy efficiently improved symptoms and haemodynamics in patients with PH in terms of CI, PVR and NT-proBNP.However, macitentan did not provide benefits, including mPAP, mRAP and SvO2.It remains uncertain whether macitentan has an impact on 6WMD.In future studies, the effect of macitentan on other cardiopulmonary function measures will need to be confirmed.In addition, macitentan therapy was safe and well tolerated.Although the long-term efficacy and safety of the medication must be more fully established, macitentan confers therapeutic benefits in patients with PAH.The effectiveness on PVR, mPAP, mRAP, mortality and other indicators still needs to be further confirmed.

T A B L E 1
Included literature information.

F I G U R E 4
Meta-analysis of the effects of follow-up versus baseline on pulmonary vascular resistance (PVR).

F
I G U R E 5 Meta-analysis of the effects of macitentan versus placebo on 6-min walk distance (6WMD).
4 | DISCUSSIONPH is characterized by pulmonary arterial remodelling.At present, if untreated, PH has a median survival of 2 years from the time of diagnosis, and the death F I G U R E 6 Meta-analysis of the effects of follow-up versus baseline on 6-min walk distance (6WMD).