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Systematic review

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Authors Wu X , Wang X , Zhang L , Pan Z , Chen F , Chen SL , Kan J , Wei Y
Journal ESC heart failure
Year 2024
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Aims: A recent guideline presented by the ESC Congress in 2022 had indicated a novel therapy targeted at pulmonary artery hypertension, known as pulmonary artery denervation (PADN), which get inspired from a laboratorial trial that could lowering the pulmonary artery pressure through the intervention on the animals. Our aim is to conduct a network meta-analysis to compare the efficacy and safety of PADN from six aspects with the current conventional therapies. Methods and results: According to the PRISMA guidance, databases including Ovid, ClinicalTrials.gov, Medline, Embase, and PubMed were searched from inception to 22 August 2023, along with a full assessment of the previous five meta-analyses. Data were extracted and curated for Bayesian network meta-analysis. The primary outcome was the change in the 6-min walking distance (6MWD) from baseline with a secondary outcome called change in mean pulmonary artery pressure (mPAP) from baseline. The four safety outcomes included risk of clinical worsening, hospitalization, mortality and severe adverse events (SAEs). The comparison is structured on a contrast model based on 65 randomized controlled trials (RCTs) on PADN and the other conventional mainstream drugs. PADN had a better effect in improving 6MWD than Placebo (−77.76 m, 95% CI: −102.04 to −54.34 m), Macitentan (−65.32 m, 95% CI: −95.34 to −36.1 m), Bosentan (−64.5 m, 95% CI: −94.7 to −35.07 m), Iloprost (−62.66 m, 95% CI: −99.48 to −27.13 m), Oxygen (−62.42 m, 95% CI: −100.01 to −25.78 m), Treprostinil (−62.01 m, 95% CI: −89.04 to −35.61 m), Riociguat (−60.59 m, 95% CI: −86.11 to −35.98 m), Selexipag (−47.2 m, 95% CI: −85.61 to −10.19 m), Sildenafil (−44.92 m, 95% CI: −74.43 to −16.15 m), or Sitaxsentan (−39.53 m, 95% CI: −78.99 to −0.76 m). PADN had a better antihypertensive effect than placebo and showed statistical significant lower risks to induce clinical worsening and re-hospitalization than treprostinil, riociguat, and placebo groups. No statistically significant difference in risk of mortality and severe adverse events was observed between PADN versus the other interventions. Conclusions: Compared with 16 types of conventional therapies and Placebo, PADN has advantage over nine single therapies and Placebo in improving 6MWD and appears to be better than two types of dual-drug combined therapies while with no statistical significance. PADN shows a favourable antihypertensive effect on mPAP and has a lower risk to trigger clinical worsening or hospitalization, while its risk on mortality and severe adverse events is still inconclusive.

Systematic review

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Journal Internal and emergency medicine
Year 2024
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The evidence for the treatment of connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH) mostly depends on subgroup or post hoc analysis of randomized controlled trials (RCTs). Thus, we performed a meta-analysis of RCTs that reported outcomes for CTD-PAH. PubMed and EMBASE were searched for CTD-PAH treatment. The selected outcomes were functional class (FC) change, survival rates, 6-min walk distance (6-MWD), clinical worsening (CW), N-terminal prohormone BNP (NT-proBNP), pulmonary vascular resistance (PVR), mean pulmonary arterial pressure (mPAP), right atrial pressure (RAP), and cardiac index (CI). The meta-analysis was conducted according to the PRISMA guidelines and registered in PROSPERO (CRD42020153560). Twelve RCTs conducted with 1837 patients were included. The diagnoses were systemic sclerosis in 59%, SLE in 20%, and other CTDs in 21%. The pharmacological interventions were epoprostenol, treprostinil, sildenafil, tadalafil, bosentan, macitentan, ambrisentan, riociguat, and selexipag. There was a significant difference between interventions and placebo in FC, 6MWD, CW, PVR, RAP, and CI that favored intervention. Our analysis showed a 39% reduction in the CW risk with PAH treatment. The short-term survival rates and mean serum NT-proBNP changes were similar between the study and control groups. Treatment for CTD-PAH had favorable effects on clinical and hemodynamic outcomes but not on survival and NT-proBNP levels. Different from the previous meta-analyses that focused on 6-MWD, time to clinical worsening, and CW as outcomes, this meta-analysis additionally reports the pooled analysis of change in FC, hemodynamic measurements (RAP, PVR, CI), and NT-proBNP, some of which have prognostic value for PAH.

Systematic review

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Journal The European respiratory journal
Year 2023
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BACKGROUND: It is currently unknown if disease severity modifies response to therapy in pulmonary arterial hypertension (PAH). We aimed to explore if disease severity, as defined by established risk-prediction algorithms, modified response to therapy in randomised clinical trials in PAH. METHODS: We performed a meta-analysis using individual participant data from 18 randomised clinical trials of therapy for PAH submitted to the United States Food and Drug Administration to determine if predicted risk of 1-year mortality at randomisation modified the treatment effect on three outcomes: change in 6-min walk distance (6MWD), clinical worsening at 12 weeks and time to clinical worsening. RESULTS: Of 6561 patients with a baseline US Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL 2.0) score, we found that individuals with higher baseline risk had higher probabilities of clinical worsening but no difference in change in 6MWD. We detected a significant interaction of REVEAL 2.0 risk and treatment assignment on change in 6MWD. For every 3-point increase in REVEAL 2.0 score, there was a 12.49 m (95% CI 5.86-19.12 m; p=0.001) greater treatment effect in change in 6MWD. We did not detect a significant risk by treatment interaction on clinical worsening with most of the risk-prediction algorithms. CONCLUSIONS: We found that predicted risk of 1-year mortality in PAH modified treatment effect as measured by 6MWD, but not clinical worsening. Our findings highlight the importance of identifying sources of treatment heterogeneity by predicted risk to tailor studies to patients most likely to have the greatest treatment response.

Systematic review

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Authors Liu C , Chen J , Gao Y , Deng B , Liu K
Journal The Cochrane database of systematic reviews
Year 2021
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BACKGROUND: Pulmonary arterial hypertension is a devastating disease that leads to right heart failure and premature death. Endothelin receptor antagonists have shown efficacy in the treatment of pulmonary arterial hypertension. OBJECTIVES: To evaluate the efficacy of endothelin receptor antagonists (ERAs) in pulmonary arterial hypertension. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, and the reference sections of retrieved articles. The searches are current as of 4 November 2020. SELECTION CRITERIA: We included randomised trials and quasi-randomised trials involving participants with pulmonary arterial hypertension. DATA COLLECTION AND ANALYSIS: Two of five review authors selected studies, extracted data and assessed study quality according to established criteria. We used standard methods expected by Cochrane. The primary outcomes were exercise capacity (six-minute walk distance, 6MWD), World Health Organization (WHO) or New York Heart Association (NYHA) functional class, Borg dyspnoea scores and dyspnoea-fatigue ratings, and mortality. MAIN RESULTS: We included 17 randomised controlled trials involving a total of 3322 participants. Most trials were of relatively short duration (12 weeks to six months). Sixteen trials were placebo-controlled, and of these nine investigated a non-selective ERA and seven a selective ERA.   We evaluated two comparisons in the review: ERA versus placebo and ERA versus phosphodiesterase type 5 (PDE5) inhibitor. The abstract focuses on the placebo-controlled trials only and presents the pooled results of selective and non-selective ERAs. After treatment, participants receiving ERAs could probably walk on average 25.06 m (95% confidence interval (CI) 17.13 to 32.99 m; 2739 participants; 14 studies; I2 = 34%, moderate-certainty evidence) further than those receiving placebo in a 6MWD. Endothelin receptor antagonists probably improved more participants' WHO functional class (odds ratio (OR) 1.41, 95% CI 1.16 to 1.70; participants = 3060; studies = 15; I2 = 5%, moderate-certainty evidence) and probably lowered the odds of functional class deterioration (OR 0.43, 95% CI 0.26 to 0.72; participants = 2347; studies = 13; I2 = 40%, moderate-certainty evidence) compared with placebo. There may be a reduction in mortality with ERAs (OR 0.78, 95% CI 0.58, 1.07; 2889 participants; 12 studies; I2 = 0%, low-certainty evidence), and pooled data suggest that ERAs probably improve cardiopulmonary haemodynamics and may reduce Borg dyspnoea score in symptomatic patients. Hepatic toxicity was not common, but may be increased by ERA treatment from 37 to 67 (95% CI 34 to 130) per 1000 over 25 weeks of treatment (OR 1.88, 95% CI 0.91 to 3.90; moderate-certainty evidence). Although ERAs were well tolerated in this population, several cases of irreversible liver failure caused by sitaxsentan have been reported, which led the licence holder for sitaxsentan to withdraw the product from all markets worldwide.  As planned, we performed subgroup analyses comparing selective and non-selective ERAs, and with the exception of mean pulmonary artery pressure, did not detect any clear subgroup differences for any outcome. AUTHORS' CONCLUSIONS: For people with pulmonary arterial hypertension with WHO functional class II and III, endothelin receptor antagonists probably increase exercise capacity, improve WHO functional class, prevent WHO functional class deterioration, result in favourable changes in cardiopulmonary haemodynamic variables compared with placebo. However, they are less effective in reducing dyspnoea and mortality. The efficacy data were strongest in those with idiopathic pulmonary hypertension. The irreversible liver failure caused by sitaxsentan and its withdrawal from global markets emphasise the importance of hepatic monitoring in people treated with ERAs. The question of the effects of ERAs on pulmonary arterial hypertension has now likely been answered.. The combined use of ERAs and phosphodiesterase inhibitors may provide more benefit in pulmonary arterial hypertension; however, this needs to be confirmed in future studies.

Systematic review

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Authors Petrovič M , Locatelli I
Journal Journal of comparative effectiveness research
Year 2020
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Aim: No network meta-analysis has been conducted to study efficacy of drug therapies specific for treatment of pulmonary arterial hypertension in treatment-naive patients only. Methods: Randomized controlled trials on pulmonary arterial hypertension-specific drug therapies were searched and a Bayesian network meta-analysis was performed. The 6-min walking distance (6MWD) and all-cause mortality were efficacy outcomes, whereas discontinuation due to adverse events was a safety-related outcome. Results: Analysis included 3.713 patients from 21 trials. Combination of ambrisentan and tadalafil showed the greatest impact on 6MWD, followed by epoprostenol and intravenous treprostinil (high dose). The latter two demonstrated marked effect size on mortality, although not statistically significant. Conclusion: According to 6MWD, ambrisentan/tadalafil combination was considered as most effective among all comparisons. Prospero ID: CRD42019110832. © 2020 Future Medicine Ltd.. All rights reserved.

Systematic review

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Authors Lin H , Wang M , Yu Y , Qin Z , Zhong X , Ma J , Zhao F , Zhang X
Journal Pulmonary pharmacology & therapeutics
Year 2018
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PURPOSE: This network meta-analysis (NMA) is designed to compare the efficacy and tolerability of various therapies and combinations for pulmonary arterial hypertension (PAH). METHOD: We conducted a systematic search in databases PubMed, Embase, and Cochrane Library. Treatment efficacy and tolerability were compared by synthesizing direct and indirect evidence. The surface under the curve ranking area was utilized to rank multiple interventions. RESULT: A total of 43 randomized clinical trials were included in our NMA. With regard to efficacy outcomes, including 6 min walking distance (6MWD), functional class amelioration (FCA), death, clinical worsening (CW), pulmonary vascular resistance (PVR), mean pulmonary artery pressure (mPAP), cardiac index (CI), and mean right atrial pressure (mRAP), endothelin receptor antagonists (ERA), phosphodiesterase 5 inhibitor (PDE-5Is), ERA combined with PDE-5Is (EAP), and prostacyclin analogs (PGI) combined with ERA (PAE) performed better than others. Meanwhile PAP and PGE demonstrated better than others in tolerability. Overall, EAP and PAE showed good efficacy and were well-tolerated among all therapies. CONCLUSION: Overall, we recommend EAP as the optimal choice for patients with PAH in clinical practice and PAE as suboptimal in view of their desirable performance in efficacy. Most of the combination therapies performed better than monotherapies.

Systematic review

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Authors Wang S , Yu M , Zheng X , Dong S
Journal Drug delivery
Year 2018
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Pulmonary arterial hypertension (PAH) can be relieved by pharmacological interventions, especially the targeted drug, which is classified into endothelin receptor antagonist, phosphodiesterase 5 inhibitor, prostaglandin I2, soluble guanylate cyclase stimulator and selective non-prostanoid prostacyclin receptor agonist. To solve the contradictions existing in reported trials and provide a comprehensive guideline for clinical practice. PubMed, Embase, Cochrane library, and clinicaltrials.gov were searched. The basic information about the article, trial, arm, intervention, and the detailed data of outcome, including 6 minutes walking distance (6MWD) change, WHO functional class (FC) improvement, Borg dyspnea score (BDS) change, cardiac index (CI) change, mean pulmonary arterial pressure (mPAP) change, mean right arterial pressure (mRAP) change, pulmonary vascular resistance (PVR) change, clinical worsening, hospitalization, death, severe adverse events (SAEs), and withdrawal were extracted. The rank of treatments was estimated. 10,230 cases provided the firsthand comparison data about targeted drugs for treating PAH. For 6MWD, ambrisentan + tadalafil, vardenafil, and sildenafil + bosentan were better than others. Epoprostenol, macitentan, and sildenafil represented a greater WHO FC improvement. Vardenafil and treprostinil were better for BDS. So were bosentan + epoprostenol and bosentan alone for CI. Iloprost plus bosentan, bosentan + epoprostenol, and epoprostenol were better for mPAP. Iloprost plus bosentan, bosentan alone, and selexipag could reduce PVR. Sildenafil, epoprostenol, and vardenafil had the highest probability to reduce the incidence of death and withdrawal. To conclude, vardenafil and iloprost + bosentan showed relatively better performance in both efficacy and safety. However, the therapeutic choice should be made according to both the feature of each therapy and the individual condition.

Systematic review

Unclassified

Authors Duo-Ji MM , Long ZW
Journal International Journal of Cardiology
Year 2017
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BACKGROUND: Endothelin receptor antagonists (ERAs) such as ambrisentan, sitaxsentan, bosentan and macitentan are primary drug therapies for pulmonary arterial hypertension (PAH) patients. However, the optimal drugs for PAH remained controversial due to heterogeneous nature of randomized control trials (RCTs). METHODS: Apart from traditional meta-analysis, network meta-analysis (NMA) was performed in this study for multiple comparisons among PAH therapies. The 6 minute walking distance (6MWD) and clinical worsening were efficacy outcomes whereas serious adverse effects (SAE) and all-cause discontinuation were acceptability outcomes. The weighted mean difference (WMD) and odds ratio (OR) along with their 95% confidence interval (95% CI) or 95% credible interval (95% CrI) were used to evaluate the positive and negative effects of these therapies on PAH patients. RESULTS: By synthesizing direct evidence from 10 studies with a total number of 2172 patients, we discovered that all of the four PAH therapies significantly increased the average 6MWD in comparison to the placebo (P-value<0.05). Moreover, bosentan and ambrisentan both showed significant association with a decrease in the risk of clinical worsening compared to placebo. Regarding of all-cause discontinuation, ambrisentan is the only therapy which was significantly associated with a risk decrease compared to placebo. However, there was no sufficient evidence suggesting significant difference in any efficacy or acceptability outcomes between any two of the PAH therapies (P-value>0.05). CONCLUSION: Ambrisentan could be considered as the most appropriate therapy among the four ERAs for PAH patients. Bosentan also behaved well, but it is not as safe as ambrisentan.

Systematic review

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Journal Chest
Year 2017
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Background We conducted a systematic review and network meta-analysis to examine comparative efficacy and tolerability of pharmacologic interventions for pulmonary arterial hypertension (PAH). Methods MEDLINE, the Cochrane Register, EMBASE, CINAHL, and clinicaltrials.gov were searched (January 1, 1990 to March 3, 2016). Randomized controlled trials (RCTs) studying the approved pharmacologic agents endothelin receptor antagonists (ERA), phosphodiesterase inhibitors (PDE5i), the oral/inhaled (PO/INH) and IV/subcutaneous (SC) prostanoids, and riociguat and selexipag, alone or in combination, for pulmonary arterial hypertension (PAH) and reporting at least one efficacy outcome were selected. Results Thirty-one RCTs with 6,565 patients were selected. In network meta-analysis, when compared with a median placebo rate of 14.5%, clinical worsening was estimated at 2.8% with riociguat (risk ratio [RR], 0.19; 95% CI, 0.05-0.76); at 3.9% with ERA + PDE5i (RR, 0.27; 95% CI, 0.14-0.52), and at 5.7% with PDE5i (RR, 0.39; 95% CI, 0.24-0.62). For improvement in functional status, when compared with 16.2% in the placebo group, improvement in at least one New York Heart Association/World Health Organization (NYHA/WHO) functional class was estimated at 81.8% with IV/SC prostanoids (RR, 5.06; 95% CI, 2.3211.04), at 28.3% with ERA + PDE5i (RR, 1.75; 95% CI, 1.05-2.92), and at 25.2% with ERA (RR, 1.56; 95% CI, 1.22-2.00). Differences in mortality were not significant. Adverse events leading to discontinuation of therapy were highest with the PO/INH prostanoids (RR, 2.92; 95% CI, 1.68-5.06) and selexipag (RR, 2.06; 95% CI, 1.04-3.88) compared with placebo. Conclusions Currently approved pharmacologic agents have varying effects on morbidity and functional status in patients with PAH. Future comparative effectiveness trials are warranted with a focus on a patient-centered approach to therapy. Registration PROSPERO CRD42016036803 © 2016 American College of Chest Physicians

Systematic review

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Journal Annals of the American Thoracic Society
Year 2017
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RATIONALE: Trials investigating use of lower tidal volumes and inspiratory pressures for patients with acute respiratory distress syndrome (ARDS) have shown mixed results. OBJECTIVES: To compare clinical outcomes of mechanical ventilation strategies that limit tidal volumes and inspiratory pressures (LTV) to strategies with tidal volumes of 10-15 mL/kg among patients with ARDS. METHODS: Systematic review and meta-analysis of clinical trials investigating LTV mechanical ventilation strategies. We used random effects models to evaluate effect of LTV on 28 day mortality, organ failure, ventilator-free days, barotrauma, oxygenation and ventilation. Our primary analysis excluded trials for which the LTV strategy was combined with the additional strategy of higher positive end-expiratory pressure (PEEP), but these trials were included in a stratified sensitivity analysis. We performed meta-regression of tidal volume gradient achieved between intervention and control groups on mortality effect estimates. We used GRADE methodology to determine the quality of evidence. RESULTS: Seven randomized trials involving 1481 patients met eligibility criteria for this review. Mortality was not significantly lower for patients receiving a LTV strategy (33.6%) as compared to control strategies (40.4%) [RR 0.87 (95% CI 0.70-1.08), I2 = 46%], nor did an LTV strategy significantly decrease barotrauma or ventilator-free days when compared to a lower PEEP strategy. Quality of evidence for clinical outcomes was downgraded for imprecision. Meta-regression showed a significant inverse association between larger tidal volume gradient between LTV and control groups and log odds ratios for mortality (β -0.1587, p=0.0022). Sensitivity analysis including trials that protocolized a LTV/high PEEP co-intervention showed lower mortality associated with LTV [9 trials and 1629 patients; RR 0.80, (95% CI 0.66-0.98), I2 =46%]. Compared with trials not using a high PEEP co-intervention, trials using a strategy of LTV combined with high PEEP showed a greater mortality benefit [RR 0.58 (95% CI 0.41-0.82), p for interaction = 0.05]. CONCLUSIONS: The trend toward lower mortality with LTV ventilation in the primary analysis and the significant relationship between the degree of tidal volume reduction and the mortality effect together suggest, but do not prove, that LTV ventilation improves mortality among critically ill adults with ARDS.