Rationale and Design of the Effect of Ivabradine on Exercise Tolerance in Patients With Chronic Heart Failure (EXCILE-HF) Trial　― Protocol for a Multicenter Randomized Controlled Trial ―

Abstract

Background: A high resting heart rate is an independent risk factor for mortality and morbidity in patients with cardiovascular diseases. Ivabradine selectively inhibits the funny current (I_f) and decreases heart rate without affecting cardiac conduction, contractility, or blood pressure. The effect of ivabradine on exercise tolerance in patients with heart failure with reduced ejection fraction (HFrEF) on standard drug therapies remains unclear.

Methods and Results: This multicenter interventional trial of patients with HFrEF and a resting heart rate ≥75 beats/min in sinus rhythm treated with standard drug therapies will consist of 2 periods: a 12-week open-label, randomized, parallel-group intervention period (standard drug treatment+ivabradine group and standard drug treatment group) to compare changes in exercise tolerance between the 2 groups; and a 12-week open-label ivabradine treatment period for all patients to evaluate the effect of adding ivabradine on exercise tolerance. The primary endpoint will be the change in peak oxygen uptake (V̇O₂) during the cardiopulmonary exercise test from Week 0 (baseline) to Week 12. Secondary endpoints will be time-dependent changes in peak V̇O₂ from Week 0 to Weeks 12 and 24. Adverse events will also be evaluated.

Conclusions: The EXCILE-HF trial will provide meaningful information regarding the effects of ivabradine on exercise tolerance in patients with HFrEF receiving standard drug therapies and suggestions for the initiation of ivabradine treatment.

Heart failure (HF) is a major cause of morbidity and mortality and is a global public health problem.¹ Standard HF drug therapies, such as β-blockers, angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers and mineralocorticoid receptor antagonists, have been established to reduce mortality and morbidity in patients with HF with reduced ejection fraction (HFrEF).^2,3 However, regardless of these therapies, patients with chronic HF gradually deteriorate with repeated acute exacerbations, ultimately leading to death.^2,3

Ivabradine, a hyperpolarization-activated cyclic nucleotide-gated channel blocker, selectively inhibits I_f, the cardiac pacemaker current in the sinus node, thereby reducing the heart rate without affecting cardiac conduction, contractility, repolarization, or blood pressure.⁴ The Systolic Heart failure treatment with the I_f inhibitor ivabradine Trial (SHIFT) found that ivabradine reduced the incidence of cardiovascular death and HF hospitalizations in patients with symptomatic HF (left ventricular ejection fraction [LVEF] ≤35%) who had a resting heart rate of ≥70 beats/min in sinus rhythm after standard therapy.⁵ The European Society of Cardiology guidelines recommend ivabradine as second-line therapy for patients with HFrEF (LVEF ≤35%) who have HF symptoms after standard HF therapy and a resting heart rate ≥70 beats/min in sinus rhythm.² The recent Japanese Circulation Society guidelines also recommend ivabradine for patients with HFrEF and a resting heart rate ≥75 beats/min in sinus rhythm.^3,6

The mechanisms of improvement in HF symptoms and prognosis with ivabradine are not fully understood.⁷ Some studies have suggested that ivabradine improves exercise tolerance in patients with HF.^8–11 However, these reports have primarily focused on ischemic HF,^8–10 have been single-center studies,^8,10 have compared ivabradine with fixed doses of β-blockers,^9,10 and have included low proportions of patients (50–60%) on standard β-blocker therapy. Thus, some questions remain, specifically: (1) does ivabradine improve exercise tolerance earlier than β-blockers after the start of treatment; (2) does the effect of ivabradine increase over time; and (3) what contributes to the improvement in exercise tolerance by ivabradine?

Therefore, the effect of ivabradine on exercise tolerance in patients with HFrEF on standard HF therapies remains unclear. In the Effect of Ivabradine on Exercise Tolerance in Patients With Chronic HF (EXCILE-HF) trial, we will investigate the effect of ivabradine on exercise tolerance using cardiopulmonary exercise testing (CPX) in patients with HFrEF and a resting heart rate ≥75 beats/min in sinus rhythm treated with standard HF drug therapies, including β-blockers, in a clinical practice setting.

Methods

Patients

The EXCILE-HF trial will enroll patients with chronic HF who are in New York Heart Association (NYHA) Class II or III with an LVEF of ≤40% and a resting heart rate (sinus rhythm) of ≥75 beats/min on 12-lead electrocardiography even after standard HF therapies with the same dose of HF drugs for at least 4 weeks. The inclusion and exclusion criteria are provided in Table 1.

Table 1. Main Inclusion and Exclusion Criteria

Main inclusion criteria

1. Age ≥20 years

2. NYHA functional class II or III and having remained in the same class for at least 4 weeks

3. Sinus rhythm with resting heart rate of ≥75 beats/min on 12-lead electrocardiography

4. Unchanged standard HF treatmentA and dosages of HF medication for at least 4 weeks

5. LVEF of ≤40%, documented within the previous 6 months

Main exclusion criteria

1. Congenital heart disease

2. Severe mitral stenosis or regurgitation

3. Critical aortic valve stenosis or regurgitation

4. Active myocarditis

5. Permanent atrial fibrillation or atrial flutter

6. Sick sinus syndrome, sinoatrial block, or second- or third-degree atrioventricular block

7. Cardiac resynchronization therapy started within the previous 24 weeks

8. Pacemaker with an atrial or ventricular pacing (excluding biventricular pacing) percentage of >40% or an atrial or ventricular pacing threshold of ≥60 beats/min

9. Symptomatic or continuous (≥30 s) ventricular arrhythmia with no ICD

10. Congenital long QT syndrome or a family history of long QT syndrome

11. Electrical cardioversion (excluding electrical cardioversion with an ICD) within the previous 24 weeks

12. Stroke or transient ischemic attack within the previous 4 weeks

13. Myocardial infarction or coronary revascularization (PCI or CABG) within the previous 8 weeks

14. Scheduled for cardiovascular surgery

15. Severe or uncontrolled hypertension (SBP >180 mmHg or DBP >110 mmHg in a sitting position)

16. Hypotension (SBP <90 mmHg or DBP <50 mmHg in a sitting position)

17. Severe liver disease, serious chronic pulmonary disease, neurological or orthopedic restrictions on exercise testing, and pregnancy

^AStandard heart failure (HF) medications include β-blockers, angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers, mineralocorticoid receptor antagonists, sodium-glucose cotransporter 2 inhibitors, angiotensin receptor-neprilysin inhibitor, and digoxin. Standard non-pharmacological HF treatments include implantable cardioverter-defibrillator (ICD) and/or cardiac resynchronization therapy and cardiac rehabilitation. CABG, coronary artery bypass grafting; DBP, diastolic blood pressure; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association; PCI, percutaneous coronary intervention; SBP, systolic blood pressure.

Study Design

The EXCILE-HF trial will be a multicenter interventional study of patients with HFrEF and will consist of 2 periods, namely a 12-week open-label, randomized, parallel-group intervention period (standard HF treatment+ivabradine group and standard HF treatment group) and a 12-week open-label treatment period (Figure). Patients will be randomized 1 : 1 using a minimization method based on the allocation factors of age at the time of informed consent (≤55, 56–70, and ≥71 years) and peak oxygen uptake (V̇O₂) during Visit 2 CPX (≤14, >14–18, and >18 mL/kg/min) using a web-based dynamic random allocation system (CapTool^®Cloud; Mebix, Inc., Tokyo, Japan). On the day of CPX, the investigator will promptly access the web-based allocation system to finalize the case registration and allocation and obtain the allocation result. If patients in the standard HF treatment group do not meet the indication for ivabradine at Week 12, they will finish the study at Week 12.

Figure.

Schematic representation of the study design. BNP, B-type natriuretic peptide; CPX, cardiopulmonary exercise testing; HF, heart failure.

The initial dose of ivabradine is 2.5 mg orally twice daily. After initiation, the dose is adjusted at intervals of at least 2 weeks to maintain the target resting heart rate while tolerability is monitored. If the resting heart rate exceeds 60 beats/min, the dose is increased by 2.5 mg twice daily, up to 7.5 mg twice daily. If the resting heart rate is between 50 and 60 beats/min, the dose is maintained. If the resting heart rate is <50 beats/min or bradycardia-related symptoms (e.g., dizziness, malaise, hypotension) are observed, the dose is decreased by 2.5 mg twice daily, or discontinued when patients are on 2.5 mg twice daily.

The period for patient enrollment in the EXCILE-HF trial was from January 2021 to December 2022, and the study is expected to be completed in June 2023. The study will be conducted according to the ethical principles stated in the Declaration of Helsinki and the Clinical Trials Act in Japan. Ethics approval has been obtained from The Jikei University Certified Review Board, Tokyo, Japan, and written informed consent will be obtained from all individuals prior to enrollment.

Endpoints

The primary endpoint will be treatment efficacy, measured as changes in peak V̇O₂ from Week 0 to Week 12 of treatment between the standard HF treatment+ivabradine group and the standard HF treatment group in patients with HFrEF based on CPX. Secondary endpoints will be changes over time in peak V̇O₂ from Week 0 to Weeks 12 and 24 to reveal the effects of ivabradine added at different time points on exercise tolerance. The comparisons of interest will be as follows: (1) the difference in the change in peak V̇O₂ from Week 0 to Week 24 between the standard treatment+ivabradine group and the standard treatment group; (2) the difference in the change in peak V̇O₂ from baseline to Week 12 in the standard HF treatment+ivabradine group and that from Week 12 to Week 24 (the standard treatment+ivabradine period) in the standard HF treatment group; and (3) the difference in the change in peak V̇O₂ from Week 0 to Week 12 and that from Week 12 to Week 24 in the standard HF treatment+ivabradine group. The CPX procedure is described in the Supplementary File. Other explanatory endpoints are listed in Table 2.

Table 2. Endpoints

Primary endpoint

Change in peak V̇O2 from Week 0 (baseline) to Week 12 based on CPX

Secondary endpoint

Changes over time in peak V̇O2 (from Week 0 to Weeks 12 and 24) based on CPX

Exploratory endpoints

1. Resting heart rate (12-lead electrocardiography)

2. NYHA functional classification

3. Plasma BNP concentration

4. Blood pressure and pulse rate

5. CPX parameters (other than peak V̇O2):

AT, RCP, heart rate (at rest, at the initiation of warm-up exercise, at the AT point, at the RCP point, at peak, at completion of cool-down exercise), R, V̇E/V̇CO2, V̇E/V̇O2, V̇E vs. V̇CO2 slope, PETCO2, PETO2, TV-RR relationship, RR threshold, Ti/Ttot, breathing reserve, SpO2, oscillatory ventilation, OUES, peak V̇O2/HR, work rate (watts), and V̇O2/HR jump-up phenomenon

6. Echocardiographic parameters:

LVDd, LVDs, IVST, LVPWT, LVEDV, LVESV, LVEF, E/A, DT, E/e′, LAD, LA volume, RVSP, TAPSE, IVC diameter, mitral regurgitation (qualitative), and tricuspid regurgitation (qualitative)

7. Grip strength measurement

8. Quality of life survey

Safety endpoints

1. Adverse events

2. Risks specified in the risk management plan:

Important identified risks: bradycardia, photopsia and blurry vision, atrioventricular block, atrial fibrillation, and QT prolongation

Important potential risks: supraventricular tachyarrhythmia (excluding atrial fibrillation) and ventricular arrhythmia

3. Blood testing:

Hematology: red blood cell count, hemoglobin level, white blood cell count, and platelet count

Blood biochemistry: total protein, albumin, urea nitrogen, creatinine, estimated glomerular filtration rate, total bilirubin, aspartate aminotransferase, alanine aminotransferase, sodium, potassium, and chloride

4. 12-lead electrocardiography: heart rate, PQ, QRS, QT, and QTc

AT, anaerobic threshold; BNP, B-type natriuretic peptide; CPX, cardiopulmonary exercise testing; DT, deceleration time of the E velocity; E/A, ratio of the E- and A-wave maximum velocities; E/e′, ratio of the E-wave maximum velocity and early diastolic velocities of the septal mitral annulus; IVC, inferior vena cava; IVST, interventricular septum thickness; LA, left atrial; LAD, left atrial diameter; LVDd, left ventricular diastolic dimension; LVDs, left ventricular diastolic dimension; LVEDV, left ventricular end-diastolic volume; LVEF, left ventricular ejection fraction; LVESV, left ventricular end-systolic volume; LVPWT, left ventricular posterior wall thickness; NYHA, New York Heart Association; OUES, oxygen uptake efficiency slope; PETCO₂, end-tidal carbon dioxide tension; PETO₂, end-tidal oxygen tension; R, gas exchange ratio; RCP, respiratory compensation point; RR, respiratory rate; RVSP, right ventricular systolic pressure; SpO₂, percutaneous oxygen saturation; TAPSE, tricuspid annular plane systolic excursion; Ti/Ttot, ratio of inspiratory time to total respiratory cycle time; TV, tidal volume; V̇E vs. CO₂ slope, minute ventilation vs. carbon dioxide production slope; V̇E/V̇CO₂, ventilatory equivalent for carbon dioxide; V̇E/V̇O₂, ventilatory equivalent for oxygen; V̇O₂, oxygen uptake; V̇O₂/HR, oxygen pulse.

The safety endpoints will include all adverse events and abnormal laboratory findings. Adverse events may be mild, moderate, or severe and may be caused by something other than the drug or therapy administered (Table 2).

Assessments

Subjective symptoms, objective findings, and NYHA class will be examined at each visit via questionnaire forms, inspections, palpation, auscultation, percussion, and other means. Vital signs (e.g., blood pressure and pulse rate), clinical laboratory tests (including hematology, biochemistry, and plasma B-type natriuretic peptide concentrations), and physiological function testing (including 12-lead electrocardiography, echocardiography, CPX, and grip strength measurements) will be evaluated. Quality of life surveys using the EQ-5D-5L (Japanese version) will also be administered at registration, Week 12, and Week 24.

Sample Size

Based on previous research,⁸ we assumed that the effect size in this study would be ≥0.8. To determine the target sample size, an effect size of 0.83 in a meta-analysis¹¹ was used as a reference value. Given that approximately 5% of patients in a Phase III trial in Japan drop out at Week 12,¹² we predicted the effect size in this study to be 0.77, assuming a comparative incidence of missing value imputation. A sample size large enough to detect a significant difference in the amount of change in peak V̇O₂ during CPX at Week 12 (3 months) was calculated with a significance level of 2-sided 5% (one-sided 2.5%) and a power of 80%, which resulted in 28 patients in each group. Therefore, the target sample size in this study was set at 30 patients in each group for a total of 60 patients.

Details regarding data collection and statistics are provided in the Supplementary File.

Discussion

The HF guidelines recommend ivabradine for patients with symptomatic HFrEF and a high resting heart rate ≥70 beats/min (or ≥75 beats/min in Japan) despite standard HF drug therapies.^4,5 Ivabradine and β-blockers both decrease heart rate. However, there is a difference between ivabradine and β-blockers in their effects on hemodynamics other than sinus rate reduction. In an experimental study using dogs, ivabradine (1 mg/kg, i.v.) and atenolol (1 mg/kg, i.v.) both reduced the heart rate at rest and during treadmill exercise (−30%) and prolonged the left ventricular (LV) diastolic time.¹³ However, under atrial pacing (125 beats/min at rest and 250 beats/min during exercise), the LV diastolic time was reduced (prolonged ejection duration), and myocardial oxygen consumption was lower with atenolol treatment than with ivabradine treatment. The maximum change in LV pressure (dP/dt_max), a measure of LV contractility, was reduced by atenolol treatment, but not ivabradine treatment, compared with control.¹³ These results suggest that β-blockers have a negative inotropic effect, whereas ivabradine does not.

In a study examining the hemodynamic effects of a single cross-over dose of ivabradine 30 mg, propranolol 40 mg, and placebo in healthy subjects, ivabradine reduced heart rate to the same degree as propranolol, but did not change the blood pressure or cardiac index during the head-up tilt test or during the ergometer exercise stress test compared with placebo.¹⁴ Conversely, propranolol decreased both the blood pressure and cardiac index during the head-up tilt test compared with placebo, although there was no significant change during the ergometer exercise stress test compared with placebo.¹⁴ These results indicate that ivabradine, but not β-blockers, can compensate for a decrease in preload because, unlike β-blockers, ivabradine has no direct negative altering effect on the myocardium, which is an advantage from a hemodynamic standpoint.

Beta-blocker therapy improves exercise tolerance and prognosis in patients with HFrEF in the long term, but in the short term it attenuates exercise tolerance through decreased blood pressure and tissue blood flow, including decreased muscle blood flow, which may be a limitation of dose titration in some HF patients. Ivabradine is expected to improve exercise tolerance in an early stage because it does not have these negative effects of β-blockers. In the EXCILE-HF trial we will evaluate whether there are differences in the improvement in exercise tolerance between the addition of ivabradine to β-blockers and β-blockers, and examine the hemodynamic effects on echocardiography,¹⁵ muscle strength (grip strength), and neurohumoral factors (B-type natriuretic peptide). In addition, as a secondary evaluation, we will examine whether the effect of ivabradine on exercise tolerance improves over time, from 3 to 6 months, and whether there are differences in the effect of ivabradine on exercise tolerance between patients who receive ivabradine as soon as it is indicated and those who receive it after 3 months of β-blocker therapy.

There are some methodological limitations of this study. Blinding will be difficult due to the obvious heart rate-suppressing effect of ivabradine, and this study is an open-label trial. Every effort will be made to ensure that outcome assessors, laboratory technicians, data managers, and statisticians will be kept blinded to the treatment allocation of the patients.

Conclusions

The EXCILE-HF trial will provide meaningful information regarding the effects of ivabradine on exercise tolerance and hemodynamics in patients with HFrEF receiving standard HF drug therapies and suggestions for the initiation of ivabradine treatment.

Acknowledgments

The authors thank Emi Sawada (Clinical Pharmacology and Therapeutics, The Jikei University School of Medicine) for her project coordination and CMIC HealthCare Institute CO., LTD. for their support in conducting the trial.

Sources of Funding

The EXCILE-HF trial was funded by Ono Pharmaceutical Co., Ltd. (Osaka, Japan). The sponsor provided the study concept and information on the study drug and assisted in the preparation of information materials; however, it will not participate in the study’s implementation, data management/analysis, and publication of findings.

Disclosures

T. Shiga has received research funding and speaker fees from Ono Pharmaceutical Co., Ltd. K.K. has received speaker fees from Ono Pharmaceutical Co., Ltd. The other authors declare that they have no competing interests.

IRB Information

The study protocol was approved by The Jikei University Certified Review Board, Tokyo, Japan (Reference no. CRB3180031). This study has been registered with the Japan Registry of Clinical Trials (ID: jRCTs 031200281).

Supplementary Files

Please find supplementary file(s);

https://doi.org/10.1253/circrep.CR-22-0134

References

• 1.   Roger VL. Epidemiology of heart failure. Circ Res 2013; 113: 646–659.
• 2.   McDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach A, Böhm M, et al. 2021 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J 2021; 42: 3599–3726.
• 3.   Tsutsui H, Isobe M, Ito H, Ito H, Okumura K, Ono M, et al. JCS 2017/JHFS 2017 guideline on diagnosis and treatment of acute and chronic heart failure: Digest version. Circ J 2019; 83: 2084–2184.
• 4.   DiFrancesco D, Camm JA. Heart rate lowering by specific and selective I(f) current inhibition with ivabradine: A new therapeutic perspective in cardiovascular disease. Drugs 2004; 64: 1757–1765.
• 5.   Swedberg K, Komajda M, Böhm M, Borer JS, Ford I, Dubost-Brama A, et al. Ivabradine and outcomes in chronic heart failure (SHIFT): A randomised placebo-controlled study. Lancet 2010; 376: 875–885.
• 6.   Tsutsui H, Ide T, Ito H, Kihara Y, Kinugawa K, Kinugawa S, et al. JCS/JHFS 2021 guideline focused update on diagnosis and treatment of acute and chronic heart failure. Circ J 2021; 85: 2252–2291.
• 7.   Orasanu G, Al-Kindi SG, Oliveira GH. Ivabradine in management of heart failure: A critical appraisal. Curr Heart Fail Rep 2016; 13: 60–69.
• 8.   Sarullo FM, Fazio G, Puccio D, Fasullo S, Paterna S, Novo S, et al. Impact of “off-label” use of ivabradine on exercise capacity, gas exchange, functional class, quality of life, and neurohormonal modulation in patients with ischemic chronic heart failure. J Cardiovasc Pharmacol Ther 2010; 15: 349–355.
• 9.   Volterrani M, Cice G, Caminiti G, Vitale C, D’Isa S, Perrone Filardi P, et al. Effect of carvedilol, ivabradine or their combination on exercise capacity in patients with heart failure (the CARVIVA HF trial). Int J Cardiol 2011; 151: 218–224.
• 10.   Bagriy AE, Schukina EV, Samoilova OV, Pricolota OA, Malovichko SI, Pricolota AV, et al. Addition of ivabradine to β-blocker improves exercise capacity in systolic heart failure patients in a prospective, open-label study. Adv Ther 2015; 32: 108–119.
• 11.   Koroma TR, Samura SK, Cheng Y, Tang M. Effect of ivabradine on left ventricular diastolic function, exercise tolerance and quality of life in patients with heart failure: A systemic review and meta-analysis of randomized controlled trials. Cardiol Res 2020; 11: 40–49.
• 12.   Tsutsui H, Momomura SI, Yamashina A, Shimokawa H, Kihara Y, Saito Y, et al. Efficacy and safety of ivabradine in Japanese patients with chronic heart failure: J-SHIFT study. Circ J 2019; 83: 2049–2060.
• 13.   Colin P, Ghaleh B, Monnet X, Su J, Hittinger L, Giudicelli JF, et al. Contributions of heart rate and contractility to myocardial oxygen balance during exercise. Am J Physiol Heart Circ Physiol 2003; 284: H676–H682.
• 14.   Joannides R, Moore N, Iacob M, Compagnon P, Lerebours G, Menard JF, et al. Comparative effects of ivabradine, a selective heart rate-lowering agent, and propranolol on systemic and cardiac haemodynamics at rest and during exercise. Br J Clin Pharmacol 2006; 61: 127–137.
• 15.   Ohte N, Ishizu T, Izumi C, Itoh H, Iwanaga S, Okura H, et al. JCS 2021 guideline on the clinical application of echocardiography. Circ J 2022; 86: 2045–2119.