Rationale and Design of an Exploratory, Randomized, Open-Label, Multicenter Clinical Trial to Investigate the Efficacy of Long-Acting β2-Agonist/Long-Acting Muscarinic Antagonist on Heart Failure Complicated by Chronic Obstructive Pulmonary Disease (COPD-HF Trial)

Abstract

Background

Chronic obstructive pulmonary disease (COPD) is one of the most common comorbidities in patients with chronic heart failure (CHF). A growing number of patients are suffering from both COPD and CHF, and these conditions worsen each other. Inhaled bronchodilator therapy with long-acting muscarinic antagonist (LAMA) and long-acting β2-agonist (LABA) in combination is currently the mainstay of treatment for COPD. However, the effect of LAMA/LABA on HF with COPD remains unknown.

Methods and Results

The COPD-HF trial is a multicenter, double-arm, open-label, exploratory, investigator-initiated clinical study to investigate the effect of LAMA/LABA on HF in patients suffering from both COPD and CHF. The participants are randomly assigned (1 : 1) to the LAMA/LABA (tiotropium+olodaterol FDC (fixed-dose combination) 5/5 ug) group (once a day, 2 inhalations) or non-pharmacological treatments for COPD as a control group. The planned number of patients to be enrolled in this trial is 54 in total (27 in each group). The participants are followed up for 12 weeks with and without LAMA/LABA. The primary endpoint is the change in plasma B-type natriuretic peptide levels from the baseline to the end of this study (12 weeks).

Conclusions

The COPD-HF trial will investigate the efficacy of LAMA/LABA on HF in patients with COPD and CHF.

Chronic heart failure (CHF) continues to have a poor prognosis, and the number of patients is rising as society ages.¹ Chronic obstructive pulmonary disease (COPD) is one of the most common comorbidities in patients with CHF, with a prevalence of approximately 20–30%.² The number of patients suffering from both COPD and CHF is increasing due to aging worldwide, and the prognostic and therapeutic importance of COPD in CHF patients is well recognized. Our retrospective study also revealed the important role of COPD in the provocation of cardiovascular events in patients with CHF.³ Inhaled bronchodilators are the first-choice treatment in COPD patients with dyspnea or exercise intolerance. A previous study targeting COPD patients with CHF has reported that LAMA monotherapy significantly improves left ventricular ejection fraction and reduces plasma B-type natriuretic peptide (BNP) levels.⁴ Recently, the Global Initiative for Chronic Obstructive Lung Disease 2023 report recommends dual bronchodilation with LAMA combined with LABA as the first-line therapy since the dual therapy is more effective than monotherapy.⁵ The combination therapy of LAMA and LABA (LAMA/LABA) is superior to the combination therapy of a LABA and an inhaled corticosteroid in reducing COPD exacerbations and improving forced expiratory volume in 1 s (FEV1), with no significant differences in the incidence of serious adverse events.^6,7 Furthermore, a randomized, double-blind, placebo-controlled, crossover trial targeting COPD patients with stable cardiovascular disease has shown that LAMA/LABA improves lung hyperinflation and increases left ventricular end-diastolic volume.⁸

The effect of LAMA/LABA on HF remains unknown, and it is considered highly important to determine whether treatment with LAMA/LABA for patients with COPD complicated by CHF can lead to improvement not only in COPD but also in HF. Therefore, we aimed to investigate the efficacy of LAMA/LABA on HF in patients with COPD and CHF.

Methods

Study Design

The COPD-HF trial is a phase 4, open-label, exploratory, investigator-initiated clinical study of pharmaceuticals. We recruited 12 institutes in Japan at the start of the study, which was registered with the Japan Registry of Clinical Trials (jRCT) (identifying number: jRCTs05120005) on 24/09/2020 before enrollment.

Randomization and Masking

Allocation of patients to the LAMA/LABA or non-pharmacological group (1 : 1) occurs after study enrollment confirmation using Pocock and Simon’s minimization method, considering adjustment factors, including age (≥70 or <70 years), sex and FEV1/forced vital capacity (FVC) by pulmonary functional test (≥0.6 or <0.6). An independent organization handles randomization via an automated web system. Randomization and allocation are done automatically by the web system. Participants and their clinicians are not masked to the allocated treatment.

Sample Size

In our previous study,⁴ the BNP level changed from 374±119 to 263±92 pg/mL and from 369±119 to 358±110 pg/mL in the tiotropium and observational groups, respectively. Based on those findings, to detect the 100 pg/mL difference in change in the plasma BNP level (assuming a standard deviation of 120 pg/mL) with a two-sided 5% significance level and 80% power would require 24 patients per group. Therefore, we set 54 patients in total, considering 10% dropout during the study.

Eligibility Criteria and Consent to Participate

Patients will be confirmed to have met all of the inclusion criteria and none of the exclusion criteria (Table 1). After the initiation of the trial, we deleted the inclusion criterion of patients with functional residual capacity (FRC) ≥120% predicted since few Japanese patients meet this criterion, and its deletion does not affect the efficacy endpoints. All eligible participants must provide written informed consent before enrollment.

Table 1.

Eligibility Criteria for the COPD-HF Trial

Inclusion criteria

1) Patients with CHF※1 and COPD※2 who are >40 years old at the time of informed consent

2) Patients with personal written consent

※1Patients with any of the following items are defined as those with CHF:

a) Patients who meet the Framingham heart diagnostic criteria

b) NYHA functional class II, III or IV within 3 months before informed consent

c) Plasma BNP levels ≥40 pg/mL or plasma NT-pro BNP levels ≥125 pg/mL within 3 months before informed consent

d) Patients treated with standard medication following the guideline for the treatment of CHF with clinically stable condition at 4 weeks

※2Patients with any of the following items are defined as those with COPD:

EEV1/FVC <70% by pulmonary function test with inhaled β-stimulants

Exclusion criteria

1) Patients who have already received LAMA or LABA for COPD

2) Patients who cannot agree to the cessation of smoking

3) Patients with an allergic history of tiotropium or olodaterol

4) Patients with a history of other severe respiratory diseases (asthma, etc.)

5) Patients with dysuria (due to benign prostatic hyperplasia, etc.)

6) Patients were diagnosed with angle closure glaucoma

7) Patients with acute HF (use of intravenous cardiotonic, diuretic, and/or antiarrhythmic drugs) or NYHA functional class IV at the time of registration or administration

8) Patients undergoing dose adjustment of digitalis, diuretics, aldosterone antagonists, cardiotonic drugs and antiarrhythmic drugs from 2 weeks before the start of administration

9) Patients with lethal arrhythmia (sustained ventricular tachycardia lasting ≥30 s or ventricular fibrillation)

10) Patients using mechanical circulatory support devices

11) Patients waiting for heart transplantation

12) Patients waiting for cardiac surgery

13) Patients within 6 months after onset of acute coronary syndrome, within 3 months after percutaneous coronary intervention or within 6 months after open heart surgery

14) Patients who started cardiac resynchronization therapy within 6 months

15) Patients with severe renal dysfunction (eGFR <15 mL/min/1.73 m2) or undergoing maintenance hemodialysis or peritoneal dialysis

16) Patients with severe liver dysfunction (T.Bil ≥10 mg/dL, AST, ALT ≥500 IU/L, >5-fold ALP normal upper limit, PT ≤40%, bleeding tendency, liver failure symptoms such as consciousness disorder, fulminant hepatitis, cirrhosis, liver tumor, Jaundice >6 months, Grade A equivalent to “Severity classification criteria for side effects of pharmaceuticals”)

17) Patients with decreased white blood cell count (<2,500/L) or platelet count (<80,000/L)

18) Patients in a serious clinical condition and who are expected to live for <3 years

19) Patients with possible alcohol or drug abuse

20) Patients who are pregnant or possibly pregnant

21) Patients who don’t agree with contraception during the study

22) Patients who are breastfeeding

23) Patients who have been enrolled in other clinical trials at the same time as this study (excluding observational studies)

24) Patients who are judged by the investigator or sub-investigators not to be suitable for participation in the study

ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BNP, B-type natriuretic peptide; CHF, chronic heart failure; COPD, chronic obstructive pulmonary disease; EEV1/FVC, forced expiratory volume in 1 s/forced vital capacity; eGFR, estimated glomerular filtration rate; HF, heart failure; LAMA, long-acting muscarinic antagonist; LABA, long-acting β2-agonist; T.Bil, total bilirubin; NT-proBNP, N-terminal pro-brain natriuretic peptide; NYHA, New York Heart Association; PT, prothrombin time.

Participation Timeline

Figure 1 and Figure 2 show the study flowchart and detailed time schedule, respectively. The study participants were enrolled in December 2021, and the follow-up period will end in April 2025. The number of patients enrolled as of the date of manuscript submission is 42.

Figure 1.

Study design of the COPD-HF trial. COPD, chronic obstructive pulmonary disease; FDC, fixed-dose combination; LAMA/LABA, long-acting muscarinic antagonist/long-acting β2-agonist.

Figure 2.

Schedule of enrolment, interventions and assessments. All study visits will occur during routine clinical follow-up visits. ^※1The value of visit 1 can be substituted. ^※2Add BNP to the measurement items. BNP, B-type natriuretic peptide; CAT, COPD assessment test; CBC, complete blood count; CHF, chronic heart failure; COPD, chronic obstructive pulmonary disease; CRP, C-reactive protein; IL-6, interleukin-6; KCCQ, Kansas City Cardiomyopathy Questionnaire; mMRC, modified Medical Research Council Dyspnea Scale; NYHA, New York Heart Association; TNF-α, tumor necrosis factor-α.

Interventions and Procedures

The 54 patients received either LAMA/LABA (Spiolt® Respimat®, once a day, 2 inhalations, tiotropium + olodaterol FDC 5/5 ug) as the investigational group or non-pharmacological treatments for COPD as the control group. Smoking cessation guidance, recommended in the COPD guideline of the Japanese Respiratory Society, is provided to both groups.⁹ The study treatment will be continued for 12 weeks.

Endpoints

The primary endpoint of this study is the change in plasma BNP level from the baseline to the end of the study (12 weeks). The secondary endpoints are shown in Table 2.

Table 2.

Secondary Endpoints

Secondary endpoints

1. Change in plasma BNP levels (baseline, after 4 weeks)

2. Change in KCCQ score (baseline, after 12 weeks)

3. Change in CAT score (baseline, after 12 weeks)

4. Change in mMRC dyspnea scale (baseline, after 12 weeks)

5. Change in pulmonary function tests (FEV1, percent predicted FEV1, FVC, percent predicted FVC, FRC, percent predicted FRC) (baseline, after 12 weeks)

6. Change in laboratory measurements (high-sensitivity CRP, fibrinogen, IL-6, TNF-α) (baseline, after 12 weeks)

7. Change in echocardiographic parameters (LV diastolic dimension, LV systolic dimension, percent fractional shortening, LV ejection fraction, left atrium dimension, inferior vena cava, tricuspid pressure gradient, transmitral flow velocity pattern, early diastolic filling velocity [E], atrial filling velocity, deceleration time, mitral annulus velocity [e′], E/e′) (baseline, after 12 weeks)

8. Incidence of death from any cause (after 12 weeks)

9. Incidence of cardiovascular events (defined as cardiovascular death, hospitalization for HF, composite of cardiovascular death or hospitalization for HF) (after 12 weeks)

CAT, COPD Assessment Test; CRP, C-reactive protein; FRC, functional residual capacity; IL-6, interleukin-6; KCCQ, Kansas City Cardiomyopathy Questionnaire; LV, left ventricular; mMRC, modified Medical Research Council; TNF-α, tumor necrosis factor-α. Other abbreviations as in Table 1.

Monitoring and the Independent Safety Monitoring Committee

Off-site monitoring, including source document verification, is planned. The independent safety monitoring committee will review the safety report and judge continuation of the study, change of trial protocol or early termination.

Statistical Analysis

Analysis Population Primary and secondary endpoints will be analyzed using the intention-to-treat principle. Safety outcomes will be analyzed for subjects who received ≥1 study treatment.

Summary of Demographic and Other Characteristics Demographic and other characteristics will be summarized for each group using appropriate statistical measures.

Analysis of Primary Outcome Plasma BNP levels at baseline, 4, and 12 weeks will be summarized using appropriate statistical measures (mean, standard deviation, median, range). Changes from baseline at 4 and 12 weeks will also be summarized. Changes at 12 weeks will be compared between groups using a mixed-effects model, with baseline BNP levels as a covariate. The difference in changes between groups, with a 95% confidence interval, will be calculated. Sensitivity analyses will be conducted using a generalized estimating equation.

Analysis of Secondary Outcomes Using the same methods, changes in plasma BNP levels from baseline at 4 weeks will be compared between groups. Other secondary outcomes will be summarized for baseline and 12 weeks. Changes from baseline to 12 weeks will also be summarized. Analysis of covariance (ANCOVA) with baseline values as a covariate will compare changes between groups. Differences, with 95% confidence intervals, will be calculated. Survival analysis (Kaplan-Meier and proportional hazards model) will be used for overall mortality and cardiovascular events.

Analysis of Safety Outcomes Adverse events will be summarized by severity and causal relationship, with incidence rates calculated. Other safety outcomes will be summarized using appropriate statistical measures.

Other Considerations A two-sided significance level of 0.05 will be used for hypothesis testing, with 95% confidence intervals. Missing primary endpoint data will be summarized, and appropriate methods applied as needed after assessing missing data frequency and reasons.

Discussion

The COPD-HF trial is designed to test whether LAMA/LABA improves HF in patients with COPD and CHF. The results of this study may provide clinically supportive evidence that treatment with LAMA/LABA for COPD-complicating CHF can lead to improvement not only in COPD but also in HF.

COPD and CHF share common risk factors and pathophysiological processes and act synergically as negative prognostic factors. Smoking, in particular, represents the greatest risk factor for both COPD and CHF. Inflammation triggered by smoking is the primary cause of COPD, resulting in dysfunction of the peripheral airways and destruction of alveolar structures.¹⁰ This damage results in the loss of elastic recoil, leading to lung overinflation and increased residual volume.¹¹ Smoking also induces systemic inflammation, which adversely affects the cardiovascular system. Chronic inflammation accelerates arteriosclerosis progression and heightens the risk of CHF. Associations have been reported between cardiovascular events in COPD patients and C-reactive protein levels,¹² highlighting systemic inflammation as a significant contributor to both COPD and HF. Furthermore, airway obstruction and lung hyperfiltration are associated with cardiac diastolic filling in patients with COPD.¹³

Timely intervention in COPD treatment is critical, given its role as an independent risk factor for the development of CHF and cardiovascular death associated with CHF.¹⁴ LAMA/LABA improves obstructive impairment and lung hyperinflation and substantially enhances exercise tolerance.^15,16 A clinical study showed that LAMA/LABA combination therapy decreased plasma levels of tumor necrosis factor-α after 12 weeks of treatment.¹⁷ The potential benefits of LAMA/LABA in preventing lung hyperinflation, improving cardiac diastolic filling and reducing inflammatory cytokines suggest implications for CHF management. Thus, although LAMA/LABA therapy demonstrates therapeutic efficacy in COPD, its direct effects on CHF warrant investigation.

BNP has been widely used as a surrogate endpoint for HF and cardiovascular events. We have reported that the plasma BNP levels non-linearly predicted the day of occurrence of clinical events in patients with CHF, and the evaluation of BNP levels predicts the occurrence probability of cardiovascular outcomes.¹⁸ Previous studies have also reported on the plasma BNP levels as an outcome measure, with changes in the plasma BNP levels evaluated over a short period, such as within 3 months.¹⁹ Thus, we determined the primary endpoint as the change in the plasma BNP levels from baseline to 12 weeks after treatment.

The COPD-HF trial will clarify the efficacy of LAMA/LABA on HF in patients with COPD and CHF.

Funding

This work was supported by Boehringer Ingelheim Co. Limited.

Conflict of Interest

Boehringer Ingelheim Co. will not have any role in the analysis or interpretation of the results of this study.

H.H., S.I., H.F., M.S., Y.A., K.F., D.F., Y.H., M.H., N.I., M.I., Y.I., T.N., T.S., S.T., M.Y. and M.K. have nothing to disclose. C.I. and M.W. reports speaker honoraria from Nippon Boehringer Ingelheim, outside the submitted work.

S.I. is a member of the Editorial Team of Circulation Reports.

Ethical Approval

This study complies with the Declaration of Helsinki and Japan’s Clinical Trials Act. The protocol was approved by the Certified Review Board of Osaka Metropolitan University (CRB5200004).

Data Availability

The deidentified participant data will not be shared.