Comparative effectiveness of Statins for Chronic Obstructive Pulmonary Disease Patients with Pulmonary Hypertension: systematic review and network meta-analysis

doi:10.21203/rs.3.rs-4927551/v1

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Comparative effectiveness of Statins for Chronic Obstructive Pulmonary Disease Patients with Pulmonary Hypertension: systematic review and network meta-analysis

https://doi.org/10.21203/rs.3.rs-4927551/v1

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Introduction and objectives: Statins may effectively treat PH-COPD, but current guidelines do not endorse their use. This study aims to assess the comparative effectiveness and safety of Statins in adult patients with pulmonary hypertension associated with chronic obstructive pulmonary disease (PH-COPD) through a systematic review and network meta-analysis.

Material and methods: We searched 8 databases for randomized controlled trials (RCTs) involving Statins in individuals with PH-COPD from inception to July 1, 2024. We assessed bias using the ROB 2.0 tool and evaluated evidence quality with the CINeMA framework. We employed a Bayesian network meta-analysis approach to assess outcomes including pulmonary artery pressure, exercise tolerance, lung function, oxygenation parameters, inflammatory markers, and vasoactive substances. Using RStudio and other software, we generated forest plots, league tables, and SUCRA curves to evaluate both direct and indirect comparisons.

Results: We analyzed data from 41 RCTs involving 3,606 participants. Our analysis revealed that all 5 statins were effective in reducing Systolic Pulmonary Artery Pressure (sPAP) compared to standard treatment(ST). Rosuvastatin was the most effective, significantly lowering sPAP(MD=-8.8; (95%CI -11.68, -5.85)) and IL-6(MD=-16.41; 95%Cl -29.64, -3.04) and improving the 6-Minute Walk Distance (6MWD)(MD=67.03; 95%Cl 2.77, 130.86). Atorvastatin 20 mg was the most effective in improving lung function, increasing PO2, reducing inflammatory markers such as TNF-α and hs-CRP, and lowering ET-1. Finally, Simvastatin 20 mg+ST was identified as the most effective regimen for reducing PCO2 and increasing NO levels.

Conclusions: Our study demonstrates that statins are more effective than standard treatment for adults with PH-COPD. Rosuvastatin is the most effective at reducing sPAP. It also improves the 6MWD and lowers IL-6 levels. Additionally, statins have significantly enhanced lung function, oxygenation parameters, and inflammatory markers in PH-COPD patients, with Atorvastatin showing the best performance in these areas.

Statins

Pulmonary Hypertension

Chronic Obstructive Pulmonary Disease. Network Meta-Analysis

Systematic review

Chronic Obstructive Pulmonary Disease (COPD) is the third leading cause of death globally, following cardiovascular diseases and stroke, posing a significant public health challenge.^1,2 Over the past five decades, the prevalence of COPD has risen markedly, now affecting over 400 million people worldwide.^1,2 According to the World Economic Forum, by 2030, the global cost of COPD treatment will reach $50 trillion annually, surpassing the expenses associated with cardiovascular diseases.^2,3 Pulmonary hypertension (PH) is diagnosed in COPD patients(PH-COPD) when the mean pulmonary artery pressure (mPAP) is ≥ 25 mmHg. Severe PH-COPD is identified when mPAP is ≥ 35 mmHg or the cardiac index is below 2.0 L/min/m2.

Approximately half of COPD patients develop PH, which is associated with a poor prognosis. Without timely treatment, the average survival time for these patients is less than five years.^4,5 The 2021 Chinese guidelines for diagnosing and treating pulmonary hypertension classify PH-COPD as Group 3 PH.⁶ Recent studies have focused on targeted therapies for PH, with long-term oxygen therapy currently recommended for Group 3 PH. The 2021 COPD guidelines⁷ suggest that treatment for mild to moderate pulmonary hypertension should focus on managing acute COPD exacerbations and improving hypoxemia and hypercapnia rather than using vasodilators or targeted drugs. Long-term oxygen therapy, administered for over six months, has improved survival rates in COPD patients and reduced mPAP, likely due to the reduction of hypoxic pulmonary vasoconstriction. However, it has not proven beneficial for patients with a baseline oxygen saturation above 89%.⁸ Currently, the standard clinical approach for PH-COPD patients involves routine supportive care. This includes maintaining clear airways, facilitating expectoration, using bronchodilators, managing infections, and improving microcirculation. However, searching for safe and effective treatments for these patients remains a critical challenge.

Statins are widely used in clinical settings to lower plasma cholesterol by inhibiting HMG-CoA reductase. Recent studies have revealed that statins also offer benefits beyond lipid reduction, such as reducing inflammation, stabilizing endothelial cells, preventing pulmonary vascular remodeling, and reducing lipid oxidation.^9–16 Additionally, studies have suggested that statins may effectively treat PH-COPD, opening up new treatment possibilities.¹⁷ However, current guidelines do not endorse their use for this condition due to small sample sizes and a lack of direct comparisons among different statins. Furthermore, there is no comprehensive analysis comparing the efficacy of various statins. Therefore, further research and network meta-analyses are necessary to assess their potential benefits fully.

This study follows the PRISMA 2020 guidelines and the PRISMA-NMA extension for network meta-analyses.^18,19 It has been registered with PROSPERO (CRD42024573849), as outlined in Appendix 1.

Search strategy

We conducted a comprehensive search across multiple databases, including CKNI, Wanfang, Weipu, CBM, PubMed, Embase, Web of Science, and CENTRAL, to find randomized controlled trials (RCTs) on statins for PH-COPD patients, covering each database from inception to July 1, 2024. We also manually searched ClinicalTrials.gov and reviewed references from selected articles and related systematic reviews. Two reviewers independently selected the studies, resolving discrepancies with a third reviewer. The full search strategy is detailed in Appendix 2.

Eligibility criteria

Eligible RCTs focused on PH-COPD, including cases with cor pulmonale. Trials assessed any commercially available statin against a placebo, standard treatment(STs), or both in the control group. Control groups could include consistent additional medications, typically oxygen therapy, bronchodilators, expectorants, and antibiotics. Statin interventions had to last more than four weeks. Only RCTs published in peer-reviewed journals were included, excluding conference abstracts, duplicates, crossover designs, and non-English or non-Chinese publications.

Screening process

We imported the retrieved items from the databases into EndNote 20, eliminated duplicates, and integrated them with results from additional sources. The screening process comprised three stages. Initially, two reviewers independently assessed the articles based on their titles, including those with uncertain relevance. The selected articles were summarized in the second stage, and any disagreements were addressed through discussion and consultation with a third reviewer. In the final stage, articles with appropriate titles and abstracts were meticulously reviewed against the established inclusion and exclusion criteria.

Data extraction

For each eligible study, we systematically collected data using a pre-designed template, including the title, first author, publication date, study location, and methodology (randomization, blinding, allocation concealment, outcome data completeness, selective reporting). We also gathered demographic details (age, sample sizes, sex ratios, inclusion/exclusion criteria, COPD stages, baseline sPAP and intervention specifics (type of statin, dosage, treatment duration, control group interventions).

Our evaluation focused on six outcomes: pulmonary artery pressure, exercise tolerance, lung function, oxygenation parameters, inflammatory markers, and vasoactive substances. Pulmonary artery pressure(sPAP, mPAP), exercise tolerance(6-Minute Walk Distance (6MWD)), lung function(FVC, FEV1, FEV1/FVC), and Oxygenation Parameters(PO2, PCO2) were treated as primary outcomes, while inflammatory markers(TNF-a, hs-CRP, IL-6) and vasoactive substances(NO, ET-1) were secondary outcomes. We assessed the safety of interventions by reviewing the incidence of adverse events. Two reviewers conducted Data extraction independently, with any discrepancies resolved through consultation with a third reviewer.

Quality assessment of evidence

We assessed the risk of bias in the included trials using the Cochrane Risk of Bias tool (RoB 2.0).²⁰ This tool evaluates five key areas: randomization process, adherence to intended interventions, management of missing data, consistency of outcome measurements, and reporting of pre-specified outcomes. Proper procedures in these domains indicate a low risk of bias, while issues suggest a high risk. Two reviewers independently conducted the bias assessment, resolving discrepancies by consensus. We used the CINeMA (Confidence in Network Meta-Analysis) framework to evaluate the quality of evidence from our network meta-analysis. CINeMA examines the certainty of evidence across six domains: within-study bias, reporting bias, indirectness, imprecision, heterogeneity, and inconsistency. Each domain was meticulously assessed to ensure a thorough evaluation of the evidence.^{21, 22}

Methods for evidence synthesis

This network meta-analysis used a Bayesian framework to integrate direct and indirect evidence, enabling a thorough comparison and ranking of multiple treatments. We assessed transitivity by comparing clinical and methodological variables between studies providing direct and indirect evidence.²³ Consistency within closed loops and the entire network was evaluated using node-splitting and design treatment interaction models.^23–25 For both continuous and dichotomous outcomes, we employed random-effects models to calculate mean differences (MD) with 95% confidence intervals (CIs) and Odds Ratios (OR) with 95% credible intervals (CrIs). We assessed heterogeneity using the I² statistic, with values above 50% indicating significant heterogeneit.²⁶ Indirect comparisons employed Bayesian network meta-analysis with Markov chain Monte Carlo (MCMC) methods, involving 20,000 burn-ins and 50,000 iterations with a thinning interval of 10. Summary estimates for pairwise comparisons were derived, and treatment effects were ranked using Surface Under the Cumulative Ranking Curve (SUCRA) values based on posterior probabilities.²⁷

Literature selection and study characteristics

We began with 449 records from our database search. After removing 191 duplicates, we reviewed 258 titles and abstracts, discarding 194 records. This left us with 64 full-text articles for a detailed assessment. Following our inclusion criteria, we identified 41 RCTs involving 3,606 patients as suitable for our study (see Figure 1). These trials were conducted in three countries, with sample sizes ranging from 16 to 80 participants and intervention durations between 1 and 12 months (see Appendix 3, Table S3.1). From the publications reviewed, we identified five statin medications. Our network analysis then compared these five statins, all approved by regulatory authorities (see Appendix 3, Table S3.2).

Risk of bias, certainty of evidence, and consistency

Appendix 4 provides an overview of the risk of bias for each trial. A major issue was the insufficient details regarding blinding methods for participants, researchers, and assessors, as well as the absence of data loss reports. Of the 41 trials reviewed, the summaries of those with a low risk of bias are: 37 studies (90.2%) for randomization, 35 studies (85.3%) for adherence to interventions, 38 studies (92.6%) for missing outcome data, 40 studies (97.5%) for outcome measurement, and 38 studies (92.6%) for reporting results. Overall, 5 studies (12.1%) exhibited a high risk of bias, and 2 (4.8%) raised concerns about potential bias.

Our evaluation of the consistency between direct and indirect evidence shows high agreement across all comparisons, illustrated in density and convergence plots (Appendix 6 and Appendix 7). The I² results indicate no significant heterogeneity within the network, with most comparisons showing low heterogeneity (Appendix 5). Using CINeMA, we found most pairwise comparisons had low confidence levels, with a few showing moderate to high confidence (Appendix 8). All networks complied with the transitivity principle, ensuring the validity of indirect comparisons (Appendix 8, Table S8.1). Additionally, the funnel plots showed no asymmetry (Appendix 9). This comprehensive analysis underscores the robustness and reliability of our findings.

Pulmonary artery pressure

For sPAP reduction, the network meta-analysis included 33 trials with 2,816 participants. Compared to ST, all 5 statins significantly reduced sPAP levels in adults with PH-COPD (Figure 2). Rosuvastatin 10mg combined with ST showed the most substantial reduction in sPAP (MD=-8.8; (95%CI -11.68 to -5.85); SUCRA 91.5%; high-confidence evidence), followed by Atorvastatin 10mg with ST (MD=-8.21; (95%CI -11.49 to -4.87); SUCRA 85.8%; high-confidence evidence), and Pravastatin 40mg (MD=-6.01; (95%CI -11.81 to -0.21); SUCRA 61%; low-confidence evidence). Among the different statins, Rosuvastatin 10mg combined with ST resulted in a significantly more significant reduction in sPAP compared to Atorvastatin 20mg with ST, Simvastatin 20mg with ST, and Simvastatin 40mg with ST (Appendix 12, Table S12.1). According to CINeMA, the overall quality of evidence for sPAP was mainly moderate to high (Appendix 8, Table S8.2).

In contrast, for the reduction of mPAP, only 6 trials were included in the network meta-analysis. No significant differences were observed between statins and ST in reducing mPAP (Figure 3). Further details are provided in Appendix 11 and 12 (FigureS11.1-11.2, Table S12.1-12.2).

Exercise tolerance

Based on the 6MWD assessment, a network meta-analysis was conducted, incorporating 12 RCTs with 1,119 participants. This analysis confirmed the effectiveness of all 5 different doses of statins in comparing ST (Appendix 10, Figure S10.1). Among these, Rosuvastatin 20 mg combined with ST was the most effective in enhancing 6MWD, with a MD of 67.03 (95%Cl 2.77 to 130.86) and a SUCRA of 87.9%. A detailed comparison of 6MWD results is provided in Appendix 11(Table S11.3) and Appendix 12(Table S12.3).

Lung function

The network meta-analysis examined the effects of statins on lung function through 21 studies each for FVC and FEV1. FVC studies involved 1,976 participants, while FEV1 studies included 1,868 participants. 11 studies with 1,038 participants were also analyzed for the FEV1/FVC ratio.

Atorvastatin 20mg combined with ST was found to be the most effective statin for improving FVC(MD=0.4; (95%Cl 0.21 to 0.58); SUCRA 82.2%) (Appendix 10, Figure S10.2). Rosuvastatin 10mg + ST and Simvastatin 20mg + ST also significantly improved FVC compared to ST alone. In terms of enhancing FEV1, all 4 different doses of statins were effective. Pravastatin 40mg led to the most substantial increase in FEV1(MD=0.56 (95%CI 0.27 to 0.85); SUCRA 98.7%). This was followed by Rosuvastatin 10mg + ST (MD=0.33; (95% CI 0.16 to 0.5); SUCRA 79.5%) and Atorvastatin 20mg + ST (MD=0.17; (95% CI 0.06 to 0.3); SUCRA 50.9%). For improving the FEV1/FVC ratio, Atorvastatin 20mg + ST, Rosuvastatin 10mg + ST, and Simvastatin 20mg + ST all showed significant benefits over ST alone. The SUCRA data (Appendix 11, Table S11.4-11.6) and additional tables (Appendix 12, Table S12.4-12.6) provide detailed comparisons of these outcomes.

Oxygenation Parameters

The effect of statins on oxygenation parameters was assessed through measurements of PO2 and PCO2. The network meta-analysis revealed that Atorvastatin 20mg + ST (MD=11.81; 95%Cl 2.93 to 20.78), Atorvastatin 10mg + ST (MD=11.6; 95%Cl 2.78 to 20.43), and Simvastatin 20mg + ST (MD=7.51; 95%Cl 3.71 to 11.49) all led to significant increases in PO2 levels compared to ST alone. Only Simvastatin 20mg + ST was significantly lower PCO2, with a MD of -9.59 (95%Cl -16.65 to -2.5) (see Figure S10.5, S10.6, S11.7 and S11.8; Tables S11.7, S11.8, S12.7 and S12.8).

Inflammatory markers

The effect of statins on inflammation was evaluated by measuring TNF-α, hs-CRP, and IL-6 levels. The network meta-analysis demonstrated that Atorvastatin 20mg + ST and Simvastatin 20mg + ST were effective in significantly reducing TNF-α, hs-CRP, and IL-6 compared to ST alone. Among the statins studied, Rosuvastatin 10mg + ST was found to be the most effective in lowering IL-6, with a MD of -16.41 (95%Cl -29.64 to -3.04) (refer to Figures S10.7-10.9; Tables S11.9-11.11; Table S12.9-12.11).

Vasoactive substances

The network meta-analysis assessed the effects of 5 different doses of statins on NO and ET-1 levels. The findings showed that Simvastatin 20mg + ST, Atorvastatin 10mg + ST, and Atorvastatin 20mg + ST were significantly more effective than ST alone in increasing NO and decreasing ET-1. Specifically, Simvastatin 20mg + ST was the most effective in raising NO levels, with a MD of 8.42 (95%Cl 3.66 to 12.86). Meanwhile, Atorvastatin 20mg + ST was the most effective in lowering ET-1, with a MD of -9.82 (95%Cl -13.03 to -6.6)(refer to Figures S10.10-10.11; Tables S11.12-11.13; Table S12.12-12.13).

Adverse events

14 studies involving 947 patients monitored for adverse reactions during treatment. Of these, 7 studies reported no adverse effects, and 1 study noted that a few patients experienced nausea and vomiting. The remaining 6 studies detailed specific adverse reactions. All reported adverse events occurred in the Atorvastatin treatment groups. These included 4 cases of elevated liver enzymes, all at a dosage of 20 mg, which returned to normal after dose reduction. Additionally, 3 cases of upper abdominal discomfort did not affect the continuation of treatment, 4 cases of muscle pain, and 3 cases of gastrointestinal issues. Specific management measures for these reactions were not provided. Due to the limited data, a network meta-analysis could not be conducted for these adverse effects.

Sensitivity analyses and meta-regressions

To test the robustness of our results, we performed a sensitivity analysis by excluding one study at a time from each group. No single study was found to affect the outcomes significantly. As shown in Appendix 13, the sensitivity analysis results were consistent with the primary findings, confirming their robustness. We also conducted a meta-regression analysis to evaluate the impact of potential baseline effect modifiers on the primary outcomes. Factors such as the baseline sPAP, gender, and age were assessed. None of these factors significantly influenced the primary outcomes (Appendix 14).

Principal findings

This network meta-analysis thoroughly assesses the efficacy and safety of 9 different statin doses for treating adults with PH-COPD. The statins evaluated include Atorvastatin, Fluvastatin, Pravastatin, Rosuvastatin, and Simvastatin. We analyzed data from 41 RCTs involving 3,606 participants, focusing on key outcomes such as pulmonary artery pressure, exercise tolerance, lung function, oxygenation parameters, inflammatory markers, and vasoactive substances. Our analysis revealed that all 5 statins were effective in reducing sPAP compared to ST. Rosuvastatin was the most effective, significantly lowering sPAP and IL-6 and improving the 6MWD. Rosuvastatin was particularly effective at 10 mg for the first two outcomes and at 20 mg for enhancing 6MWD. Atorvastatin at 20 mg was the most effective in improving lung function, increasing PO2, reducing inflammatory markers such as TNF-α and hs-CRP, and lowering ET-1. Although Pravastatin at 40 mg had the highest SUCRA score for improving FEV1, its findings were based on a single study, which limits its reliability. Finally, Simvastatin 20 mg + ST was identified as the most effective regimen for reducing PCO2 and increasing NO levels.

Strengths and limitations of this study

This study is the most comprehensive and current systematic review and network meta-analysis of statins for patients with PH-COPD. It compares the effectiveness of nearly all available statins in reducing pulmonary artery pressure and evaluates their impact on exercise tolerance, lung function, and blood gas levels (PO2, PCO2). The study also examines effects on inflammatory markers (TNF-α, hs-CRP, IL-6) and vasoactive substances (NO, ET-1), using the CINeMA quality assessment method to ensure result reliability.

However, the study has several limitations. Many RCTs included were not pre-registered, with unclear details on blinding and concealment. Most studies are in Chinese, with only five in English, raising concerns about the applicability of findings to other ethnic groups despite sensitivity analyses for regional biases. There are also limited studies on some statins and specific outcomes. For example, while Atorvastatin and Simvastatin are well-represented, Fluvastatin, Pravastatin, and Rosuvastatin have fewer studies, and direct comparisons among these statins are lacking. This limitation affects the strength of the evidence, and the small number of studies on outcomes like TNF-α, IL-6, PO2, and PCO2 further weakens the results. Therefore, findings should be interpreted with caution.

Comparisons with other studies

Previous network meta-analyses have offered limited comparisons of statins for PH-COPD, often focusing on only a few statins.^28,29 This study fills that gap by incorporating comprehensive, up-to-date data on various statins, aiding clinicians in selecting the best treatment. Our findings support earlier analyses on statin effectiveness in COPD patients and extend them by evaluating the best-performing statins, comparing various doses, and assessing safety profiles.³⁰ Unlike many existing studies, we thoroughly explore dose-response relationships, providing detailed insights into the efficacy and safety of a broad range of statins, thus enhancing clinical decision-making.

Policy implications

This study evaluates the effectiveness of statins in treating adult patients with PH-COPD. Among the statins, Rosuvastatin was the most effective in reducing sPAP and improving 6MWD, especially at higher doses. Atorvastatin showed the greatest improvement in lung function. Statins also demonstrated anti-inflammatory effects, with notable efficacy from Atorvastatin 20 mg and Rosuvastatin 10 mg. Additionally, combining statins with standard treatments significantly improved PO2 and PCO2 levels compared to standard treatments alone. Unlike some targeted therapies, statins effectively reduce pulmonary artery pressure without compromising oxygen saturation, offering a promising approach for managing COPD.

Our study demonstrates that statins are more effective than standard treatment for adults with PH-COPD. Among the statins, Rosuvastatin is the most effective at reducing sPAP. It also improves the 6MWD and lowers IL-6 levels. Additionally, statins have significantly enhanced lung function, oxygenation parameters, and inflammatory markers in PH-COPD patients, with Atorvastatin showing the best performance in these areas. Further research with larger sample sizes and higher quality is needed to confirm these findings and evaluate the safety of different statins.

Ethics approval and consent to participate

No ethical approval was required as this study synthesized evidence on published RCTs that included no confidential data and personal information about the patients.

Consent for publication

All authors have read and approved the final manuscript

Availability of data and materials

No additional data and materials are available

Funding

This work was fnancially supported by Sanming Project of Medicine in Shenzhen (No.SZZYSM202211006).

Declaration of Competing Interest

The authors have no financial or proprietary interests in any material discussed in this article.

Acknowledgments

We thank all authors of previous studies who kindly provided additional information and data of their studies for this meta-analysis

CRediT authorship contribution statement

XGB, HWR and DXL conceived this study. XGB developed and implemented the systematic review, under the supervision of DXL. HWR provided the statistical analysis plan for the study and performed data analysis. OXY, CL and TXX performed study search, screening, and extraction of data, whereas HWR reviewed the work. XGB and HWR wrote the first draft of the current review, with FXZ providing input to the final draft. All authors read and approved the final manuscript.

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No competing interests reported.

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Comparative effectiveness of Statins for Chronic Obstructive Pulmonary Disease Patients with Pulmonary Hypertension: systematic review and network meta-analysis

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Abstract

Figures

Introduction

Materials and Methods

Search strategy

Eligibility criteria

Screening process

Data extraction

Quality assessment of evidence

Methods for evidence synthesis

Results

Discussion

Principal findings

Strengths and limitations of this study

Comparisons with other studies

Policy implications

Conclusions

Declarations

References

Additional Declarations

Supplementary Files

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