Ivabradine Use and Exercise Capacity Post-Atrial Switch Repair for Transposition of Great Arteries

Abstract

Background

There are few proven therapies for improving exercise capacity in patients with transposition of the great arteries who have undergone an atrial switch repair.

Objectives

The objective of the study was to evaluate the effect of heart rate lowering using ivabradine on exercise capacity and quality of life in this cohort.

Methods

In this single-center, randomized, double-blind, crossover study, patients were randomized to ivabradine or placebo for 4 weeks then crossover treatment for 4 weeks. A cardiopulmonary stress test and quality of life assessment were performed at baseline then at weeks 4 and 8. Estimates of difference were described using a mixed effects model.

Results

A total of 19 patients were eligible and 10 patients completed the study. Compared to placebo, ivabradine treatment was associated with lower heart rate at baseline (65 ± 3 beats/min on ivabradine vs 79 ± 5 beats/min on placebo, difference −14.6 [−24, −5]; P = 0.008) and at peak exercise (131 ± 7 beats/min vs 146 ± 7 beats/min, difference −15.3 [−24, −6]; P = 0.003). Peak oxygen consumption was 20.4 ± 1.2 mL/kg/min on ivabradine vs 19.2 ± 1.2 mL/kg/min on placebo (difference +1.2 [−0.09, 2.6]; P = 0.06). Peak oxygen pulse was higher on ivabradine compared to placebo (12.5 ± 1.2 vs 10.7 ± 1.2 mL/beat, difference +1.7 [0.9, 2.6]; P = 0.002). Visual analog score was 73.5 ± 5.6 on ivabradine vs 62.5 ± 5.6 on placebo (mean difference 11.0 [−1.6, 23.6]; P = 0.08). One patient developed symptomatic bradycardia and one patient experienced phosphenes.

Conclusions

Ivabradine use in patients with transposition of the great arteries and atrial switch repair lowered peak heart rate with exercise and was associated with a higher oxygen pulse. (Effect of Ivabradine use on exercise capacity in patients with transposition of the great arteries [TGA] post atrial switch repair; ACTRN12621000196842)

Central Illustration

Background

Adults with transposition of the great arteries who have undergone an atrial switch repair have a reduced exercise capacity compared to the normal population.1, 2, 3 Exercise intolerance occurs due to inability of the systemic right ventricle to augment cardiac output with exercise2, 3, 4; reasons include poor systolic contractile reserve,^5,6 impaired ventricular filling, abnormal atrioventricular (AV) coupling,⁷ a disproportionate increase in heart rate on exercise,⁸ and myocardial ischemia.⁹

There is little evidence regarding optimal medical therapy for adults with a systemic right ventricle, including those post–atrial switch repair. Small, retrospective studies have reported an improvement in NYHA functional class in atrial switch patients taking beta-blockers10, 11, 12 and one study of atrial switch patients with implantable cardioverter defibrillators (ICDs) in situ observed fewer ventricular arrhythmias with beta-blockers.¹³ A possible mechanism for benefit relates to heart rate lowering, particularly with exertion, which affords more efficient AV transport and potentially reduces myocardial ischemia.¹³

Ivabradine, as a selective sinus node slowing agent with few side effects, may be better tolerated than beta-blockers, particularly in younger patients. There is evidence supporting ivabradine use in stable coronary disease^14,15 and in heart failure with a failing systemic left ventricle16, 17, 18 but this agent has not been studied in adults with congenital heart disease.

The objective of this study was to assess the effect of ivabradine on exercise capacity in patients with transposition of the great arteries (TGA) post-atrial switch repair. We hypothesized ivabradine would improve exercise capacity in this cohort via heart rate reduction with more efficient AV transport.

Methods

Trial design

This single-center, randomized, double-blind, placebo-controlled, crossover study was conducted at the Royal Melbourne Hospital, Australia. The study complies with the Declaration of Helsinki and the research protocol was approved by the local human research ethics and governance committees. Informed consent was obtained from all subjects before participation in the study. The study is registered with the Australia and New Zealand Clinical Trials Registry (ACTRN12621000196842).

Participants

Participants were identified through the Royal Melbourne Hospital Adult Congenital Cardiac Clinic. Adults (age >18 years as at time of recruitment) with TGA who had undergone a previous atrial switch operation were eligible. Exclusion criteria included: decompensated heart failure; inability to exercise; atrial fibrillation or not in sinus rhythm; resting bradycardia (heart rate <60 beats/min); severe hepatic impairment; coprescription with strong cytochrome P450 inhibitors or QT prolonging medications; pregnancy or lactation; rare hereditary problems of galactose intolerance, LAPP lactase deficiency or glucose-galactose malabsorption (lactose excipient in tablet); remote living location; and inability to comply with medication prescription. Eligible patients were provided with a detailed explanation of the study at the time of outpatient visit and written informed consent was obtained.

Intervention

Baseline assessment included 12-lead electrocardiogram (ECG), 24-hour Holter monitor, echocardiography, and blood tests, including full blood examination, renal function and electrolytes, liver function tests, and B-type natriuretic peptide. A cardiopulmonary stress test (CPET) and quality of life surveys were completed on day 0 before the commencement of the study drug. Patients were randomized to receive ivabradine or placebo for 4 weeks before treatment crossover for another 4 weeks (without a washout period). The study drug was commenced (at day 0 and day 28) at a dose of 5 mg bd and increased at 2 weeks (at day 14 and 42) to 7.5 mg bd if the heart rate remained more than 60 bpm on a 12-lead ECG. A 24-hour holter was performed in weeks 3 and 7. Quality of life surveys, 12-lead ECG, and cardiopulmonary stress testing were repeated after taking the study drug for 4 weeks (at day 28 and 56). The study enrollment protocol adheres to the SPIRIT 2025 statement checklist (Supplemental Table 2) and is presented in Figure 1.

Figure 1.

Study Protocol

VT = ventricular tachycardia.

Blinding and randomization

Randomization was performed by the hospital clinical trials pharmacist, who was blinded to the patient’s clinical data and acted as a third party. Patients were randomized in a 1:1 fashion to commence ivabradine or placebo using an online generator of randomly permuted blocks. The randomization sequence remained in possession of pharmacy until all data were collected. Medications were over-encapsulated to maintain blinding and labeled as A or B. The pharmacist distributed ivabradine or placebo in capsule form, identical in appearance and prepackaged in identical containers with the identification number and patient’s initials. Both patients and study personnel were, therefore, blinded to the treatment arm.

Outcomes

The primary endpoint was change in peak oxygen consumption (VO₂). Secondary endpoints included exercise duration (minutes), exercise load, VO₂ at anaerobic threshold, peak heart rate, minute ventilation/carbon dioxide production and oxygen (O₂) pulse, a noninvasive estimate of stroke volume.¹⁹ CPET was performed according to the American Thoracic Society guidelines. Patients underwent symptom-limited exercise testing on a bicycle ergometer. Work load was increased by 5 to 15 W every minute in a stepwise manner, depending on the individually predicted maximum exercise capacity. Continuous measurements of minute ventilation, VO₂, carbon dioxide production, heart rate, blood pressure, ECG, and O₂ saturations were performed during the test.

Subjects completed 2 quality of life questionnaires (12-Item Short Form Health Survey and visual analog scale (VAS) for health status) at the same time points as well as answering a question indicating whether their general wellbeing was the same, better or worse at 4 weeks and 8 weeks compared to baseline. An adverse event committee was formed.

Statistical analysis

For sample size estimation, a baseline peak VO₂ of 22 ± 5 mL/kg/m²²⁰ was assumed, and a sample size of 40 patients was anticipated to be required to obtain 80% power to show a 20% difference in peak VO₂ between ivabradine and placebo (assuming 2-sided alpha of 0.05).

For descriptive statistics, data are expressed as numbers with percentages, as mean ± SE or as median (IQR), as appropriate. For analysis of continuous outcomes, a mixed model allowing for a random effect of patient and for fixed effects of time and treatment was fitted to estimate the difference between placebo and ivabradine. The analyses assume no crossover effects. The model provides an estimate of the mean difference between ivabradine and placebo with a 95% CI for the difference, which quantifies the treatment effects. Residual plots were examined to assess assumptions of normality and constant variance of the model residuals with no concerns identified.

Analyses were performed in Minitab statistical software.

Results

Study population

A total of 39 patients were screened through the Royal Melbourne Hospital adult congenital cardiology clinic between February 2021 and April 2024 (Figure 2). Of these, 20 patients were ineligible due to: resting bradycardia (n = 10), atrial fibrillation (n = 4), remote living location (n = 4), inability to exercise owing to hemiparesis (n = 1), and medication compliance concerns (n = 1). Nine of 10 patients excluded owing to bradycardia were on a beta-blocker (sotalol, n = 5; bisoprolol, n = 3; metoprolol, n = 1).

Figure 2.

Patient Selection

Of the 19 eligible patients, 11 consented to participate in the study. One patient was withdrawn from the study during the initial 4 weeks after experiencing a ventricular arrhythmia. This 50-year-old female had severe RV dysfunction, a primary prevention defibrillator in situ and paroxysmal atrial arrhythmias, managed with sotalol. Her baseline heart rate was 70 beats/min and QTc interval was normal. Her heart rate on the trial drug was 60 beats/min with an unchanged QTc at the 2 week assessment. The patient developed symptoms consistent with a respiratory tract infection and was prescribed oral clarithromycin by her local practitioner. She had a syncopal episode 1 week later and a device check confirmed ventricular tachycardia managed with appropriate ICD therapy. The patient was unblinded (study drug was ivabradine) and withdrawn from the study having performed a baseline CPET only. The consensus of the adverse event committee was the ventricular arrhythmia primarily related to concurrent sotalol and clarithromycin use with subsequent QT prolongation.

We present findings for the 10 patients who completed the study and had CPETs when taking ivabradine and placebo. Baseline characteristics are presented in Table 1. There were no significant differences compared to those not included in the study (Supplemental Table 1). The mean age was 43.7 ± 2.4 years and half were females. All were NYHA functional class I or II. The atrial switch operation (Senning procedure, n = 6; Mustard procedure, n = 4) was performed at a mean age of 1.1 ± 0.3 years. Four patients had a device in situ (pacemaker, n = 3, ICD, n = 1).

Table 1.

Baseline Characteristics

Age, y	43.7 ± 2.4
Female	n = 5
BMI, kg/m2	28.7 ± 1.7
NYHA functional class	I, n = 4; II, n = 6
Age atrial switch (years)	1.1 ± 0.3
Septostomy as neonate	n = 7
Other surgery	n = 1
Atrial baffle intervention	n = 2
PPM in situ	n = 3
ICD	n = 1
Heart failure admission	n = 2
AF or SVT	n = 0
VT	n = 2
Echocardiography
RV function (TTE)	Normal, n = 1; mild dysfunction, n = 3; moderate dysfunction, n = 5; severe dysfunction, n = 1
TR severity (TTE)	nil, n = 1; mild, n = 5; moderate, n = 3; severe, n = 1
Hb (g/L)	145 ± 4.6
Cr (μmol/L)	76 ± 4.5
BNP (pg/mL)	82 ± 15
Medications	Beta-blocker, n = 5
	ACEI or ARB, n = 5
	ARNI, n = 1
	Spironolactone, n = 2
	DOAC, n = 1
Quality of life
SF-12 score	101.5 ± 2.5
SF-12-Physical	47.1 ± 1.3
SF-12-Mental	54.4 ± 2.8
VAS	74 ± 1.6
Cardiopulmonary stress test
Exercise duration (min)	11.0 ± 0.6
Load (W)	110 ± 11
RER	1.2 ± 0.03
Baseline heart rate (beats/min)	75 ± 3.5
Peak heart rate (beats/min)	143 ± 6.9
Peak heart rate (% predicted)	82 ± 3.8
Chronotropic reserve	68 ± 6.1
Peak VO2 (mL/kg/min)	18.5 ± 1.1
Peak VO2 (% predicted)	69.1 ± 4.8
VO2 at anaerobic threshold (% peak VO2)	66.4 ± 4.1
VE/VCO2 slope	33.9 ± 1.7
Oxygen pulse, rest (ml/beat)	3.3 ± 0.6
Oxygen pulse, peak (ml/beat)	10.6 ± 1.2
Oxygen pulse (%predicted)	87.6 ± 7.6
VE, rest (L/min)	10.4 ± 1.9
VE, peak (L/min)	67.9 ± 7.2

Values are mean ± SE.

ACEI = angiotensin converting enzyme inhibitor; AF = atrial fibrillation; ARB = angiotensin receptor blocker; ARNI = angiotensin receptor neprilysin inhibitor; BMI = body mass index; BNP = B-natriuretic peptide; Cr = creatinine; DOAC = direct oral anticoagulant; Hb = hemoglobin; ICD = implantable cardioverter-defibrillator; PPM = permanent pacemaker; RER = respiratory exchange ratio; RV = Right ventricle; SF-12 = 12-Item Short Form Health Survey; SVT = supraventricular tachycardia; TR = tricuspid regurgitation; TTE = transthoracic echocardiogram; VAS = visual analog scale; VE = minute ventilation; VE/VCO₂ = minute ventilation/carbon dioxide production; VO₂ = oxygen consumption; VT = ventricular tachycardia.

An echocardiogram was performed in all at a median of 1 month before study commencement; systemic RV function was reduced in 9 patients. The mean fractional area change was 28% ± 2%, mean S’ was 6.8 ± 0.7 cm/s; mean tricuspid annular plane systolic excursion was 12 ± 2 mm. An magnetic resonance imaging had been performed in 6 patients (median 15 months prior); mean RV ejection fraction was 49% ± 1% and mean left ventricular (LV) ejection fraction was 65% ± 6%. A catheter study had been performed in 6 patents (median 18 months prior) with the following values: right atrial pressure was 9 ± 1 mm Hg, mean pulmonary pressure was 18 ± 3 mm Hg, pulmonary capillary wedge pressure was 12 ± 3 mm Hg and mean right ventricular end-diastolic volume was 11 ± 2 mm Hg.

Study drug

Five patients were randomized to receive ivabradine for the first 4 weeks and 5 for the second 4 weeks. All patients started the study drug at 5 mg twice a day; a dose increase to 7.5 mg twice a day occurred at week 2 of treatment in 3 patients when taking ivabradine and 8 patients when taking placebo. Pill counts confirmed a compliance rate of 91% ± 3%.

Adverse effects occurred in 3 patients: phosphenes (n = 1 [ivabradine]); nonsustained ventricular tachycardia on holter (n = 1 [placebo]); and symptomatic bradycardia (n = 1 [ivabradine]). The patient with symptomatic bradycardia had an initial resting heart rate of 70 beats/min (on carvedilol) and was well during the first 4 weeks of the study (on placebo). Fatigue and dyspnea occurred within a few days of treatment crossover. An ECG at day 34 (ie day 6 of ivabradine) confirmed sinus bradycardia at 45 beats/min and the third CPET was expedited (performed that day). The patient ceased the study drug and was clinically improved within 48 hours.

Clinical outcomes

Clinical outcomes are presented in Table 2 according to ivabradine or placebo use. Difference in peak heart rate, peak VO₂ and O₂ pulse between ivabradine and placebo are presented in Figure 3.

Table 2.

Clinical Outcomes

	Ivabradine	Placebo	Mean Difference (Ivabradine Minus Placebo)
			Estimate	95% CI	P Value
SF-12 overall	98.8 ± 3.6	96.6 ± 3.6	2.24	−5.5 to 10.0	0.522
SF-Physical	47.3 ± 3.3	43.2 ± 3.3	4.14	−3.2 to 11.5	0.229
SF-Mental	51.5 ± 2.3	53.4 ± 2.3	−1.9	−4.9 to 1.1	0.18
VAS	73.5 ± 5.6	62.5 ± 5.6	11.0	−1.6 to 23.6	0.079
Heart rate (ECG)	64.7 ± 3.0	79.3 ± 5.2	−14.6	−24.3 to −4.8	0.008
Average HR (Holter)	63.3 ± 3.0	69.8 ± 3.0	−6.5	−17.5 to 0.13	0.05
QTc interval	441.6 ± 13.4	442.8 ± 13.2	−1.2	−16.0 to 13.6	0.85
Exercise duration (min)	11.7 ± 0.7	11.7 ± 0.7	−0.5	−0.62 to 0.52	0.85
Load (watts)	117 ± 12.4	116 ± 12.4	1.0	−10.6 to 12.6	0.85
Load % predicted	78.2 ± 5.2	79.6 ± 5.2	−1.4	−10.0 to 7.2	0.72
RER	1.2 ± 0.03	1.2 ± 0.03	−0.03	−0.07 to 0.03	0.397
Borg score - leg fatigue	7.2 ± 0.6	7.9 ± 0.6	−0.7	−1.4 to 0.01	0.048
Borg score - dyspnea	6.4 ± 0.4	6.2 ± 0.4	0.2	−0.3 to 0.7	0.397
Peak oxygen saturations (%)	94.7 ± 1.0	96.5 ± 0.75	−1.8	−4.3 to 0.65	0.13
Peak heart rate (beats/min)	131 ± 7.2	146 ± 7.2	−15.2	−24.3 to −6.3	0.004
Peak HR (%predicted)	74.4 ± 3.7	83 ± 3.7	−8.8	−13.7 to −3.9	0.003
Chronotropic reserve	59.2 ± 5.6	71 ± 5.6	−11.8	−18.7 to −4.9	0.004
Baseline SBP (mm Hg)	115.5 ± 5.0	110.5 ± 5.0	5.0	−5.5 to 15.5	0.304
Peak SBP (mm Hg)	153.0 ± 11.1	153.5 ± 11.1	−0.5	−21.9 to 20.9	0.958
Peak VO2 (mL/kg/min)	20.4 ± 1.2	19.2 ± 1.2	1.23	−0.09 to 2.55	0.064
Peak VO2 % predicted	75.4 ± 4.3	71.5 ± 4.3	3.9	−0.91 to 8.71	0.099
VO2 at anaerobic threshold	62.3 ± 3.2	64.6 ± 3.2	−2.3	−8.4 to 3.8	0.412
VE/VCO2 slope	35.1 ± 1.9	34.6 ± 1.9	0.5	−1.7 to 2.7	0.611
Oxygen pulse, rest (mL)	4.6 ± 0.5	4.5 ± 0.5	0.12	−1.1 to 0.9	0.79
Oxygen pulse, peak (mL)	12.5 ± 1.2	10.7 ± 1.2	1.7	0.9-2.6	0.002
Oxygen pulse % predicted	104.8 ± 8.6	89.6 ± 8.6	15.2	7.6-22.8	0.002
VE, rest (L/min)	11.9 ± 1.2	12.9 ± 1.2	−1.01	−3.8 to 1.8	0.43
VE, peak (L/min)	74.6 ± 7.9	71.0 ± 7.9	3.6	−0.6 to 7.8	0.08

Values are mean ± SE. ECG = electrocardiogram; HR = heart rate; RER = respiratory exchange ratio; SBP = systolic blood pressure; other abbreviations as in Table 1.

Figure 3.

Difference in Cardiopulmonary Stress Test Findings Between Placebo and Ivabradine

(A) Difference in peak heart rate (percent predicted) between placebo and ivabradine. The mean for each treatment shown in black (with SD), gray bars represent individual patients (B). Difference in peak VO₂ (mL/kg/min) between placebo and ivabradine. Peak VO₂ was higher in 8 of 10 patients when taking ivabradine compared to placebo. The mean for each treatment shown in black (with SD), gray bars represent individual patients (C) Difference in oxygen pulse at peak exercise (ml/beat) between placebo and ivabradine. The mean for each treatment shown in black (with SD), gray bars represent individual patients. VO₂ = oxygen consumption.

Exercise work load was higher than baseline (110 ± 11 W) in both placebo (116 ± 12, P = 0.05) and ivabradine groups (117 ± 12, P = 0.009). Resting heart rate was significantly lower in the ivabradine arm compared to placebo as anticipated (65 ± 3 vs 79 ± 5 beats/min; difference −15 beats/min [95% CI: −24 to −5; P = 0.008]) as was peak heart rate (131 ± 7 vs 146 ± 7 beats/min, difference −15 beats/min [95% CI: −24 to −6; P = 0.004]).

Peak VO₂ when taking ivabradine was 20.4 ± 1.2 mL/kg/min compared to 19.2 ± 1.2 mL/kg/min when taking placebo (difference +1.2 mL/kg/min [95% CI: −0.09 to 2.6; P = 0.06]) (Figure 3B). Peak VO₂ was higher in 8 of 10 patients when taking ivabradine compared to placebo. In an exploratory analysis of the patients who completed 4 weeks of each study arm as per protocol (n = 9, thus excluding 1 patient whose CPET was expedited owing to symptomatic bradycardia on ivabradine), peak VO₂ and peak VO₂ percent predicted were significantly higher when taking ivabradine compared to placebo (peak VO₂ 20.8 ± 1.3 vs 19.1 ± 1.3 mL/kg/min, P < 0.001; peak VO₂ percent predicted 74.0% ± 3.8% vs 68.1% ± 3.8%, P < 0.001). There was no significant difference in peak VO₂ nor change in peak VO₂ between those with a previous Mustard vs Senning repair.

O₂ pulse at peak exercise was significantly higher in the ivabradine group compared to placebo (12.5 ± 1.2 vs 10.7 ± 1.2 mL/beat, difference +1.7 mL/beat [95% CI: 0.9-2.6]; P = 0.002) (Figure 3C) as was O₂ pulse percent predicted (105% ± 9% vs 90% ± 9%, difference +15% [95% CI: 8-23]; P = 0.002).

Quality of life survey findings are presented in Figure 4. The VAS score was higher when taking ivabradine compared to placebo in 7 patients (VAS 74 ± 6 on ivabradine vs 63 ± 6 on placebo [mean difference +11; 95% CI: −2 to 24; P = 0.08]). When taking ivabradine, patient reported well-being compared to baseline was: better than at baseline, n = 5; no different, n = 3; and worse, n = 2 (versus when taking placebo, compared to baseline: no different, n = 7; worse, n = 3). Three patients requested to continue on the active trial medication after completion of the study owing to a perceived improvement in quality of life and exercise capacity.

Figure 4.

Difference in Quality of Life Survey Findings Between Placebo and Ivabradine

(A) Difference in VAS (visual analog scale) between placebo and ivabradine. The mean for each treatment shown in black (with SD), gray bars represent individual patients (B) Difference in SF-12 between placebo and ivabradine, The mean for each treatment shown in black (with SD), gray bars represent individual patients. SF-12 = 12-Item Short Form Health Survey.

Discussion

Summary of findings

In this single-center, randomized, double-blind crossover study of 10 patients with TGA with an atrial switch repair, ivabradine use had the intended effect of lowering baseline heart rate with a between group difference of −15 beats/min (95% CI: −24 to −5 beats/min) as well as peak heart rate on exercise (mean difference −15 beats/min; 95% CI: −24 to −6 beats/min). Peak VO₂ was higher when taking ivabradine vs placebo in 8 of 10 patients (mean peak VO₂ on ivabradine was 20.4 ± 1.2 mL/kg/min compared to 19.2 ± 1.2 mL/kg/min on placebo [P = 0.06]) (Central Illustration). One patient with a lower peak VO₂ on ivabradine had developed significant symptomatic sinus bradycardia on the study drug. O₂ pulse at peak exercise was significantly higher when taking ivabradine (105% ± 9% predicted vs 90% ± 9% predicted; P < 0.001). There was no clear difference in quality of life; however, visual analog score was higher for ivabradine compared to placebo in 7 patients.

Central Illustration.

Ivabradine use Post–Atrial Switch Repair for Transposition of the Great Arteries

Heart rate reduction with ivabradine use was associated with a higher oxygen pulse at peak exercise in this randomized crossover study of patients with transposition of the great arteries and previous atrial switch repair. Red line represents mean ± SD and orange lines represent individual patients. TGA = transposition of the great arteries.

Potential mechanisms for benefit of heart rate control in atrial switch patients

Currently, most patients born with TGA undergo an arterial switch repair to achieve anatomical correction for TGA, but a large cohort of young adults exist who underwent an atrial switch repair in childhood (from late 1950s until late 1980s), providing physiologic not anatomic correction. Issues encountered in the longer term after atrial switch repairs include: systemic right ventricular dysfunction,¹ increased risk of arrhythmia and sudden death,²¹ baffle complications, and impaired exercise tolerance.^3,4,22,23 In a study of patients who had an atrial switch repair in Toronto or Zurich,¹ the majority did not report any symptoms in their daily activities; however, peak VO₂ was reduced (<80% predicted) in 2-thirds compared to age and gender matched controls (mean peak VO₂ was 29 ± 10.5 mL/kg/min).

Poor exercise capacity primarily relates to an inability to satisfactorily increase cardiac output with exercise, contributed to by reduced systolic contractile reserve of the morphologic right ventricle^5,6 but also impaired ventricular filling secondary to abnormal AV coupling⁷ and myocardial ischemia,⁹ which increases the risk of ventricular arrhythmias in addition.

Impairment of AV coupling is a consequence of abnormal, noncompliant atria and lack of atrial contraction, which limits augmentation of ventricular preload in response to pharmacological stress or increased heart rates. The abnormal stroke volume response to exercise in this population was demonstrated in a study of 14 patients by Derrick et al.⁷ Stress by both exercise and dobutamine infusion was associated with an increase in cardiac index, improved indices of myocardial contraction, AV coupling, and isovolumic relaxation; however, there was a failure to augment stroke volume when expected to be 40% higher than resting values. This was hypothesized to relate to lack of augmentation of right ventricular filling during high heart rates (as reflected in dV/dt on echocardiography), reflective of abnormal AV transit. These results were corroborated by Fratz et al⁸ who also demonstrated a disproportionate rise in heart rate with exercise in a group of TGA/atrial switch patients compared to congenitally corrected TGA (CCTGA) patients. Presumably a greater heart rate rise with exercise occurs as a compensatory mechanism for a lack of change in stroke volume to maintain cardiac output but a disproportionate heart rate rise is counterproductive with compromise of ventricular filling. As a consequence, exercise limitation can occur in the absence of significant RV dysfunction or AV valve dysfunction in this population.

Medical therapy post–atrial switch repair for TGA

No medication has been clearly shown to improve clinical outcomes post–atrial switch repair. Small, single-center, prospective, observational studies have suggested benefit of sacubutril/valsartan and sodium glucose co-transporter 2 inhibitor use in patients with a systemic RV with improvements in 6 minute walk test distance and RV function, in particular.24, 25, 26 Other medications previously trialed include angiotensin receptor blockers (valsartan for 3 years,²⁷ losartan for 15 weeks²⁸) and angiotensin converting enzyme inhibitors (ramipril²⁹). Sudden death is the most common cause of death post atrial switch repair for TGA and often occurs on exertion, which may relate to ventricular arrhythmias triggered by myocardial ischemia in the setting of tachycardia⁹; beta-blocker use has been independently associated with a lower rate of ventricular arrhythmias in patients with TGA post atrial switch repair with implantable cardioverter-defibrillators in situ,¹³ which adds weight to the hypothesis that limitation of high heart rates is of benefit in this patient group. Beta-blockers are, however, often poorly tolerated in young patients, hence use of ivabradine in this study.

Ivabradine

Ivabradine inhibits the I_f current in the sinoatrial node, thereby reducing heart rate without affecting blood pressure or ventricular systolic function. In patients without congenital heart disease, ivabradine has been shown to be an effective antianginal medication,^14,30 to reduce major adverse cardiac events and heart failure events in patients post myocardial infarction³¹ and to improve clinical outcomes^16,32,33 as well as exercise capacity (peak VO₂)³⁴ in patients with LV systolic heart failure, in particular in those with a heart rate of 70 beats/min or more (beyond improvements observed with beta-blockers).

Although the benefit of heart rate lowering in LV failure likely relates to modulation of neurohormonal activation, a potential mechanism for benefit in the atrial switch population is improvement in AV transport through heart rate lowering by allowing more time for ventricular filling with a consequent increase in stroke volume; an increase in O₂ pulse, which is reflective of the combined effect of stroke volume and muscle O₂ extraction,^35,36 in those taking ivabradine in our study is potentially in keeping with this hypothesis. Interestingly, a meta-analysis in patients with heart failure and a systemic LV also documented an improvement in peak VO₂ with ivabradine use without a significant change in quality of life.³⁴

Based on the findings of this study, in the absence of contraindications to use, we feel it is reasonable to trial ivabradine in clinically well atrial switch patients to assess for an improvement in quality of life or exercise capacity. Ivabradine use may be considered, in addition, in atrial switch patients with heart failure, particularly if established on a beta-blocker with a heart rate in sinus rhythm more than 70 beats/min or if intolerant of beta-blockers. Those with atrial or ventricular arrhythmias should preferentially be established on beta-blockers rather than ivabradine.

Adverse effects of ivabradine

The main adverse effect of concern with ivabradine use in the atrial switch population is bradycardia, in particular given the recognized risk of sinus node dysfunction.³⁷ Symptomatic sinus bradycardia occurred in 5% to 8% of patients in the large heart failure and stable angina trials using ivabradine in a non-adult congenital heart disease population.^16,17,38 Resting bradycardia was the reason for exclusion in one-quarter of patients screened for this study; however, most were on a beta-blocker, thus a switch to ivabradine was an option if clinically indicated. Treatment with ivabradine in this study led to an average 15 beats/min reduction in heart rate at rest and on exercise; therefore, the use of a reduced initial dose (as per our study protocol) and close surveillance is warranted during the initial few weeks of treatment. Furthermore, coprescription with other rate-controlling agents in the absence of a pacemaker should be performed with caution. One patient in this study, who was also on a beta-blocker, developed severe symptomatic bradycardia on ivabradine, which was associated with a significant decline in exercise capacity, highlighting the balance between limitation of exercise-induced tachycardia and development of severe, symptomatic bradycardia.

One patient was withdrawn from the study before completion of an on-treatment stress test owing to a ventricular arrhythmia requiring ICD therapy, which likely primarily related to QTc prolongation due to concurrent sotalol and clarithromycin use. Isolated cases of torsades de pointe have been reported with ivabradine use when co-prescribed with a drug that prolongs QTc³⁹ and QTc prolongation was seen more frequently with ivabradine compared to placebo in the SIGNIFY study (1.8% vs 0.7%, P < 0.001), although this did not translate into increased risk of severe ventricular arrhythmias (0.8% vs 0.7%, P = 0.28).³⁸ The aforementioned patient was on the active study drug, thus it is feasible ivabradine use lowered the threshold for a ventricular arrhythmia but this was very unlikely to have occurred without clarithromycin use.

Ivabradine has been reported to be weakly associated with atrial fibrillation with a relative risk of 1.15 (95% CI: 1.07-1.24; P = 0.0027) in a meta-analysis of 21,571 patients.⁴⁰ Atrial fibrillation did not occur as a complication of ivabradine in this study.

Study Limitations

A smaller than anticipated sample size was achieved, limited by recruitment challenges (exacerbated by the SARS-CoV-19 pandemic) as well as exclusion owing to resting bradycardia; the small sample size limits the power of this study thus findings should be considered exploratory in nature and interpreted with caution.

The results of this study apply to a declining population with TGA who have undergone surgical palliation with an atrial switch repair and not to those who have undergone an arterial switch operation. They may, however, be extrapolated to patients with CCTGA who have undergone a ‘double switch’ repair (combined atrial and arterial switch operation).

A larger, multicenter study, inclusive of CCTGA patients who have undergone a “double switch” repair, may be of benefit to validate the findings of this study, explore subgroups who may be more likely to benefit and to further evaluate potential risks, especially arrhythmias. A comparison with other heart rate limiting medications, in particular beta-blockers, would also be of value to clarify whether the potential benefit relates solely to heart rate limitation or is specific to ivabradine use.

Conclusions

Heart rate reduction with ivabradine use was associated with a higher O₂ pulse at peak exercise in this randomized crossover study of patients with TGA and previous atrial switch repair.

Perspectives.

COMPETENCY IN MEDICAL KNOWLEDGE: Exercise intolerance in patients with TGA and atrial switch repair is common. Multiple factors are contributary, including reduced stroke volume augmentation on exertion owing to abnormal AV transport through noncontractile and noncompliant atrial baffles. There is some evidence for beta-blocker use in this setting (improved NYHA functional class, lower ventricular arrhythmia rate in those with ICDs in situ).

TRANSLATIONAL OUTLOOK: Heart rate limitation on exercise with ivabradine use was associated with improved O₂ pulse in this small, randomized, crossover study in adults with TGA and atrial switch repair. Caution should be taken in those with resting bradycardia and/or co-existent rate-controlling agent medication use in the absence of a pacemaker. Use of an initial reduced dose and close monitoring during commencement is advised. The results are exploratory and should be validated by larger studies.

Funding support and author disclosures

Funding was received via special purpose research funds at the Royal Melbourne Hospital. The authors have reported that they have no relationships relevant to the contents of this paper to disclose.