Effect of beraprost sodium on pulmonary hypertension due to left ventricular systolic dysfunction:protocol for a randomized controlled clinical trial

Li Wang ,Yu-Qi ChenLiang-Ping Zhao ,Xian-Song Chang ,Xiang LiuWen-Jing WangJian-Chang ChenWei-Ting Xu

1 Department of Cardiology,The Second Affiliated Hospital of Soochow University,Suzhou,Jiangsu Province,China

2 Department of Emergency,The Second Affiliated Hospital of Soochow University,Suzhou,Jiangsu Province,China

Abstract

Key words:beraprost;pulmonary hypertension;heart failure;pulmonary artery pressure;ejection fraction;exercise tolerance;prognosis;randomized controlled trial

INTRODUCTION

Background

Pulmonary hypertension (PH) is a refractory disease with high cost and poor prognosis including five groups according to clinical presentation,pathological findings,hemodynamic characteristics,and treatment strategy.1PH due to left ventricular systolic dysfunction (PH-HFrEF) is common with morbidity and mortality rates.2,3PH-HFrEF is characterized by backward transmission of filling pressures due to impaired left ventricular systolic function with the increased pulmonary artery wedge pressure,and may further lead to right ventricle overload and right ventricular failure.4At present,in addition to the treatment for left ventricular failure,there is still a lack of other ways to further reduce patient's pulmonary artery pressure and improve the whole heart function.

Beraprost is the first chemically stable and orally active prostacyclin analogue,and has antiplatelet and vessel-dilating effects.It is mainly used to reverse intermittent claudication and reduce the pain and cold symptoms caused by peripheral chronic arterial occlusive disease.5A small sample-sized study including severe primary pulmonary hypertension showed that oral administration of beraprost may result in long-lasting clinical and hemodynamic improvements.6The other two randomized controlled trials mainly selecting primary pulmonary hypertension patients showed that beraprost improves the exercise capacity that persists up to 3-6 months.But,there were no hemodynamic improvements or long-term outcome benefits.7,8

The pathogenesis of PH-HFrEF is completely different from that of primary pulmonary hypertension,so different therapies are used.There is a lack of related study on the use of beraprost in patients with PH-HFrEF.In this study,we gave beraprost sodium orally to patients with PH-HFrEF on the basis of routine treatment to investigate the efficacy and safety of this therapy.

Objectives

The objectives of this study are to investigate whether beraprost sodium in combination with routine treatment can further reduce pulmonary artery pressure,improve cardiac function,and reduce the incidence of heart events in patients with PHHFrEF,and evaluate the adverse drug reactions.

METHODS/DESIGN

Study design and setting

This is a prospective,multi-center,randomized,controlled clinical trial conducted at the Second Affiliated Hospital of Soochow University and the Seventh People's Hospital of Suzhou,China.This trial was registered in the Chinese Clinical Trial Registry (registration number:ChiCTR-IPR-17012961) on October 12,2017.The flow chart of this trial is given in Figure 1.The study protocol was developed based on the Standard Protocol Items:Recommendations for Interventional Trials (SPIRIT) guidelines9(Additional file 1).

Figure 1:Flow chart of the study.

Study population

Consecutively hospitalized patients with heart failure are included in this study.

Inclusion criteria

Male or female patients aged 18 to 85 years are examined by echocardiography to determine whether there is left ventricular systolic dysfunction (left ventricular ejection fraction＜45%) and PH (systolic pulmonary artery pressure＞40 mmHg).The PH-HFrEF is defined as the left ventricular ejection fraction＜45% and systolic pulmonary artery pressure (sPAP)＞40 mmHg.1All measurements are performed following the recommendations of the American Society of Echocardiography.10,11

Exclusion criteria

Patients with shock,hemorrhagic disease,severe hepatic insufficiency,acute stage of myocardial infarction,pregnancy,malignant tumor,or other types of pulmonary hypertension (such as idiopathic,connective tissue diseases,drugs,thromboembolic,chronic lung disease,portal hypertension,and congenital heart disease) are excluded.

Baseline measures

N-terminal pro-brain natriuretic peptide,leukocyte,hemoglobin,platelets,creatinine,alanine aminotransferase,glutamic oxalate aminotransferase,and serum lipid profiles including triglyceride,total cholesterol,low-density lipoprotein cholesterol,and high-density lipoprotein cholesterol are assessed using standard methods.Demographic and clinical characteristics of the recruited patients are collected from hospital case records and include age,sex,cigarette smoking status,hypertension,diabetes mellitus,and principal diagnosis.Patient's height (m) and body weight (kg) in light clothing are measured,and body mass index (kg/m2) is calculated.

Grouping and administration

After providing informed consent,the selected PH-HFrEF patients were randomly divided into routine treatment only and beraprost sodium + beraprost sodium groups.

Patients with PH-HFrEF are given beraprost sodium (Beijing Tede Pharmaceutical Co.Ltd.,Beijing,China) orally for 1 year (1 μg/kg per day,three times of administration) on the basis of routine treatment including diuretics,spironolactone,angiotensin converting enzyme inhibitors,angiotensin receptor blockers,βblockers,and digoxin.If there are no complications such as shock,severe bleeding,or severe liver function damage,the dosage of beraprost sodium is not changed.

Outcome measures

Outcome measures are assessed at baseline and at 3,6,9 and 12 months after treatment.These include general indexes (aortic systolic pressure,diastolic pressure,heart rate,and rhythm,New York Heart Association cardiac function classification,electrocardiogram),echocardiographic indexes (sPAP and left ventricular ejection fraction),6-minute walking distance,and blood parameters (N-terminal pro-brain natriuretic peptide,creatinine,alanine aminotransferase,glutamic oxalate aminotransferase,leukocyte,hemoglobin,and platelet).

Primary outcome measure

The primary outcome is the reduction rate of sPAP at 12 months after treatment compared with baseline.The reduction rate of sPAP is (sPAP at baseline - sPAP at 12 months after treatment)/sPAP at baseline ×100%.

Secondary outcome measures

The secondary outcome measures are the incidence of major adverse cardiac events (MACEs),left ventricular ejection fraction and 6-minute walking distance.The MACEs include cardiac death,heart failure readmission,myocardial infarction,and new onset of atrial fibrillation.

The time frame and measures are listed in Table 1.

Adverse events

Adverse events including severe hemorrhage (intracerebral hemorrhage,gastrointestinal hemorrhage,pulmonary hemorrhage),shock and hepatic insufficiency (alanine aminotransferase exceeded the normal upper limit by three times),are recorded.If severe adverse reactions occur,the investigators will report the details and provide urgent treatment.Whether the adverse events are drug-related is determined according to the medical history,clinical manifestations,and auxiliary examinations.

Sample size

According to the primary outcome measure,we hypothesized that the reduction rate of sPAP was 45% in the routine treatment + beraprost sodium group and 30% in the routine treatment group.Takingα= 0.05,power = 90%,and withdrawal rate = 10%,the total sample size calculated by PASS 11 software (NCSS,Silver Spring,MD,USA) was 231 cases in each group.

According to the secondary outcome measures,we hypothesized that the incidence of MACE was 10% in the beraprost sodium group,20% in the routine treatment group.Takingα= 0.05,power = 90%,and withdrawal rate = 10%,the total sample size calculated by PASS 11 software was 191 cases in each group.

Table 1:Timing of outcome measures

Therefore,the total sample size required for this study was 231 cases in each group.

Statistical analysis

The final data will be analyzed by SPSS 17.0 for Windows (SPSS Inc.,Chicago,IL,USA).The chi-square test will be used for analyzing count data,and Student'st-test (normal distribution) or Mann-WhitneyUtest (non-normal distribution) will be used for analyzing quantitative data.

The difference of reduction rate of sPAP between the routine treatment and routine treatment + beraprost sodium groups will be analyzed by Student'st-test (normal distribution) or Mann-WhitneyUtest (non-normal distribution).The chi-square test will be used to analyze the incidence of MACE between the two groups.The Kaplan-Meier method (i.e.,log-rank test) will be used for survival analysis and Cox regression will be used to evaluate independent predictors of MACE occurrence.

Data monitoring

Data summarization and case verification are conducted every 3 months.All adverse events are recorded and properly handled.Investigators should trace the adverse events until they are properly resolved or stable,and report them to the ethics committee in time.Principal investigators should review all adverse events accumulatively every 3 months,and convene a meeting among investigators to assess the risks and benefits of the study if necessary.

Investigator training

Case report forms are prepared to standardize the investigation and survey techniques and to improve the working ability and responsibility of the investigators.

Ethics and dissemination

This trial was approved by the Medical Ethics Committee of the Second Affiliated Hospital of Soochow University,China (approval number:JD-LK-2017-021-02) and are undertaken in accordance with Good Clinical Practice guidelines and theDeclaration of Helsinki.Informed consent is obtained from the patients before enrollment (Additional file 2).Patient recruitment was initiated in February 2018.Analysis of primary outcome measure will be completed in September 2021,and the study will be finished in September 2021.Dissemination plans include presentations at scientific conferences and publication in scientific journals.

DISCUSSION

PH-HFrEF is different from other types of PH in terms of pathogenesis and management.Unlike heterozygous BMPR2 mutations accounting for approximately 75% of familial pulmonary arterial hypertension,no specific genetic linkage has been identified for PH-HFrEF.2,12PH is common in patients with chronic heart failure.Up to 60% of patients with severe left ventricular systolic dysfunction develop PH,and almost all patients with severe symptomatic mitral valve disease have PH whether or not with heart failure.13,14

Management of PH-HFrEF is a systematic work.Treatment for group 1 PH (idiopathic,heritable,drugs and toxins induced,associated with connective tissue disease,etc.) in the European Society of Cardiology (ESC) and the European Respiratory Society (ERS) guidelines does not apply to patients with PH-HFrEF.1Most of the clinical findings showed that PH-specific therapies (e.g.,endothelin receptor antagonists,phosphodiesterase type 5 inhibitors,soluble guanylyl cyclase stimulators) had no effects on PH-HFrEF and some could even be regarded as harmful.15-17General therapies for heart failure including diuretics,digoxin,angiotensin-converting enzyme inhibitors and β-blockers are recommended for the treatment of PH-HFrEF.18Furthermore,identifying and treating possible causes of heart failure,such as coronary artery disease,cardiomyopathy,and heart valve disease,is important.19

Beraprost,a stable and oral prostacyclin analogue,is recommended for peripheral chronic arterial disease.5Like prostacyclin,beraprost acts on the prostacyclin receptor in platelets and vascular smooth muscle,activates adenylate cyclase,increases intracellular cAMP concentration,inhibits Ca2+influx and thromboxane A2 production,and thus plays the antiplatelet and vasodilatory effects.In addition,beraprost can increase the endothelial nitric oxide synthase and nitric oxide production in mouse and bovine aortic endothelial cells,20and suppress tumor necrosis factor-α expression in human monocytesviamitogen-activated protein kinase pathway,21which are all beneficial to vascular diseases.

Our pilot study with a small sample size showed that oral administration of beraprost sodium on the basis of routine treatment may reduce patient's sPAP,increase left ventricular ejection fraction and 6-minute walking distance.There were no cardiac death,myocardial infarction,shock,severe bleeding,and severe impairment of liver function,which indicate the great efficacy and safety of beraprost in these patients.Therefore,we designed this randomized controlled trial to investigate whether the addition of beraprost sodium on the basis of routine treatment can further reduce pulmonary artery pressure,improve cardiac function,reduce the incidence of heart events in patients with PH-HFrEF.

TRIAL STATUS

We are currently recruiting participants.

Additional files

Additional file 1:SPIRIT Checklist.

Additional file 2:Model consent form (Chinese).

Acknowledgments

We would like to thank all subjects who have agreed to participate in the study.

Author contributions

Chief investigator of this study:LPZ;coinvestigators:LW,YQC,XSC,XL,WJW,JCC,WTX;concept and design of the study:LW,YQC;manuscript drafting:LW;patient recruitment:XSC,XL,WJW;follow-ups:JCC,WTX;approval of final manuscript for publication:all authors.

Conflicts of interest

The authors declare no conflicts of interest.

Financial support

No current funding sources for this study.

Institutional review board statement

The protocol was approved by the Medical Ethics Committee of the Second Affiliated Hospital of Soochow University (approval number:JD-LK-2017-021-02).

Declaration of patient consent

The authors certify that they will obtain all appropriate patient consent forms.In the forms,the patients will give their consent for their images and other clinical information to be reported in the journal.The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity,but anonymity cannot be guaranteed.

Reporting statement

This study protocol was reported in line with the Standard Protocol Items:Recommendations for Interventional Trials (SPIRIT) guidelines.

Biostatistics statement

The statistical methods of this study were reviewed by the biostatistician of the Soochow University in China.

Copyright transfer agreement

The Copyright License Agreement has been signed by all authors before publication.

Data sharing statement

Individual participant data that underlie the results reported in this article,after deidentification will be in particular shared.Study protocol and informed consent form will be available.The data will be available immediately following publication without end date.Results will be disseminated through presentations at scientific meetings and/or by publication in a peer reviewed journal.Anonymized trial data will be available indefinitely at www.figshare.com.

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Peer review

Externally peer reviewed.

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