Abstract
Background
The potential synergistic effect of ivabradine and cardiac resynchronization therapy (CRT) in heart failure (HF) patients has rarely been studied. We aimed to evaluate the clinical benefits of ivabradine in patients with left ventricular dysfunction following CRT implantation.
Methods
Two hundred and thirty-one patients receiving CRT were consecutively enrolled between January 2014 and December 2018 from two HF centers. A total of 123 patients had left ventricular ejection fraction (LVEF) < 40% and resting sinus heart rate (HR) ≥ 75 bpm after six months of CRT implantation. Among these patients, 45 were treated with ivabradine (Group 1), and 78 did not receive ivabradine treatment (Group 2).
Results
Baseline characteristics and prescription rates of HF medications other than ivabradine were similar between the two groups. In Group 1, the mean HR decreased from 82.2 ± 11.4 bpm to 76.3 ± 10.5 bpm (p = 0.012), and the mean LVEF increased from 29.9 ± 6.5% to 38.8 ± 12.4% (p < 0.001). Atrial pacing percentage, biventricular pacing percentage, and burden of atrial fibrillation (AF) were not significantly different between the two groups during the study period. The patients’ daily physical activity increased significantly in Group 1 compared to Group 2 (Δ daily activity 0.4 ± 0.7 hours/day vs. -0.1 ± 7.2 hours/day, p < 0.001).
Conclusions
Ivabradine could effectively reduce HR and improve physical activity. It was safe to use and did not increase AF burden or affect biventricular pacing percentage in CRT recipients.
Keywords: Atrial fibrillation, Cardiac resynchronization therapy, Heart failure, Ivabradine
INTRODUCTION
Heart failure (HF) leads to high morbidity and mortality and has a tremendous adverse impact on the quality of life.1 Over-activation of the neurohumoral system is a central mechanism in the pathophysiology of HF. Evidence-based medications, including renin-angiotensin system inhibitors (RASis) and cardioselective beta-blockers are recommended as first-line therapies to reduce mortality and morbidity in HF.
Cardiac resynchronization therapy (CRT) and ivabradine therapy are considered second-line therapies based on guideline recommendations, and therefore should be considered for suitable heart failure patients with reduced ejection fraction (HFrEF) after standard HF medical therapy.2,3 The benefits of CRT as an adjunctive device modality to treat HF patients with wide QRS have been documented, however randomized studies for CRT in HF patients were mainly conducted before the wide usage of ivabradine.4,5 In the Systolic Heart failure treatment with the If inhibitor ivabradine Trial (SHIFT), similar benefits of ivabradine were observed in patients both with and without left bundle branch block.6,7 However, in the SHIFT trial, only < 1% of HF patients in the ivabradine group (n = 28) received CRT implantation, and few studies have reported the effects of ivabradine on CRT recipients.
Whether the heart rate lowering and left ventricular reverse remodeling effects of ivabradine could synergistically add to the benefit of CRT treatment is unknown. Previous studies have shown that ivabradine may increase atrial fibrillation (AF) burden. AF may decrease the percentage of biventricular pacing and hence attenuate the efficacy of CRT.8,9 The aim of this study was to evaluate the clinical effects of ivabradine in patients who received CRT implantation but who still had a left ventricular ejection fraction (LVEF) < 40% following successful CRT implantation.
METHODS
Study design and patient characteristics
In the present study, we retrospectively analyzed data from two HF centers in Taiwan. The study complied with the Declaration of Helsinki’s ethical principles and was approved by the institutional ethics committee of each hospital. No informed consent was obtained because of the retrospective study design.
The definition of HF was consistent with the European Society of Cardiology (ESC) guidelines: presentation of typical HF symptoms accompanied by HF signs caused by a structural and functional cardiac abnormality.2 Patients with New York Heart Association class II to IV HF symptoms, and LVEF of ≤ 40% were defined as having HFrEF in the current study.
Two hundred and thirty-one patients who received CRT implantation between January 2014 and December 2018 were consecutively screened. The inclusion criteria for the current study were: (1) male or female, age > 20 years old; (2) patients who received successful CRT implantation for more than six months but were still symptomatic with documented LVEF < 40%; and (3) sinus rhythm and heart rate ≥ 75 beats/min. The exclusion criteria were: (1) patients who refused medical advice or were lost to follow-up; (2) patients in whom echocardiographic LVEF improved to ≥ 40% following CRT implantation; and (3) non-sinus rhythm (atrial pacing, non-paroxysmal atrial fibrillation or atrial flutter). The flowchart of the current study is shown in Figure 1. After applying the inclusion and exclusion criteria, the patients were further classified into two groups. Group 1 patients had received ivabradine for at least six months after CRT implantation, and Group 2 patients did not receive ivabradine treatment throughout the study period. Data on baseline characteristics, vital signs, echocardiographic parameters, and concomitant HF medications were collected. Atrial pacing percentage, the burden of AF, biventricular pacing percentage, and patient activity data were extracted from the device.
Figure 1.
The flowchart of the current study. CRT, cardiac resynchronization therapy; LVEF, left ventricular ejection fraction.
Device and programming of cardiac resynchronization therapy
The CRT devices implanted in the current study were manufactured by either Medtronic or Abbott. Following CRT implantation, the patients were assigned to cardiac implantable electronic device clinics and were followed-up by specific electrophysiologists. The CRT devices were programmed into DDD mode with a low rate of 60 bpm. A-V timing and V-V timing were programmed individually to ensure maximal bi-ventricular pacing. After 2014, quadripolar LV lead was introduced and routinely implanted to all patients. An automatic optimization algorithm was utilized if available (i.e. AdaptivCRT Algorithm by Medtronic,10 and QuickOpt timing cycle optimization by Abbott11), otherwise, the electrocardiography (ECG)/ echocardiography-guided CRT optimization method was used for A-V and V-V timing programming.
Echocardiography studies
Echocardiographic studies were routinely arranged every 6-9 months to assess heart function. Echocardiographic data were collected before CRT implantation from all patients. Among the Group 1 patients, echocardiographic data were collected before the initiation of ivabradine, and 6-9 months following ivabradine treatment. Serial echocardiographic parameters were collected from the Group 2 patients. The left ventricular end-diastolic diameter was measured at end-diastole, and left ventricular end-systolic diameter and left anteroposterior atrial dimension were measured at end-systole on parasternal views. The LVEF was calculated using the biplane Simpson’s method on apical 4-chamber and 2-chamber views. Continuous-wave Doppler of the tricuspid regurgitation trace was used to measure and estimate pulmonary artery systolic pressure.
Statistical analysis
Quantitative data were expressed as mean ± standard deviation or as median and interquartile range, and categorical variables were presented as percentage. Descriptive summaries were presented for different groups of patients. The paired t-test was used for comparisons between continuous data, and the chi-square test was used for comparisons between categorical data. Event rates for HF re-hospitalizations in the two groups were estimated using the Kaplan-Meier method and compared using the log-rank test. A p-value of < 0.05 was considered statistically significant. The statistical analyses were performed using IBM SPSS Statistics 24.0 software (IBM SPSS, IBM Corp, Armonk, NY, USA).
RESULTS
Baseline characteristics
Between January 2014 and December 2018, 231 HFrEF patients who received CRT implantation at the two HF referral centers were consecutively examined. After applying the inclusion and exclusion criteria (Figure 1), a total of 123 CRT recipients (mean 66.3 years, 68.2% male, 26.8% with CRT-defibrillator) remained symptomatic with documented LVEF < 40% six months following CRT implantation and were enrolled for analysis, including 45 patients treated with ivabradine (Group 1) and 78 patients who did not receive ivabradine (Group 2). Before CRT implantation, the mean LVEF and QRS duration were 24.2 ± 6.1% and 162.3 ± 22.2 msec, respectively. Among the 123 CRT recipients, 109 (88.6%) received CRTs manufactured by Medtronic, and 14 (11.4%) received CRTs manufactured by Abbott. In addition, a device-based algorithm for AV and VV optimization was used in 47 (38.2%) patients, and ECG/echocardiography-based AV and VV optimization was used in 76 (61.8%) patients. Baseline characteristics were comparable between Group 1 and Group 2. The detailed baseline characteristics are shown in Table 1.
Table 1. Baseline characteristics of the study patients.
| Ivabradine, Gr I (n = 45) | Non-ivabradine, Gr II (n = 78) | p value | |
| Age (y/o) | 64.7 ± 15.6 | 67.1 ± 13.0 | 0.358 |
| Male gender, n (%) | 31 (68.9) | 53 (67.9) | 0.914 |
| Body mass index (kg/m2) | 26.0 ± 4.0 | 24.7 ± 3.5 | 0.072 |
| Ischemic cardiomyopathy, n (%) | 12 (26.7) | 21 (26.9) | 0.975 |
| Devices | |||
| Cardiac resynchronization therapy pacemaker | 30 (66.7) | 60 (76.9) | 0.216 |
| Cardiac resynchronization therapy defibrillator | 15 (33.3) | 18 (23.1) | |
| Comorbidities | |||
| Diabetes mellitus, n (%) | 15 (33.3) | 25 (32.1) | 0.884 |
| Hypertension, n (%) | 20 (44.4) | 39 (50.0) | 0.552 |
| Prior myocardial infarction, n (%) | 7 (15.6) | 11 (14.1) | 0.826 |
| Peripheral arterial disease, n (%) | 1 (2.2) | 4 (5.1) | 0.651 |
| Prior stroke or transient ischemic attack, n (%) | 2 (4.4) | 4 (5.1) | 0.864 |
| Paroxysmal atrial fibrillation, n (%) | 9 (20.0) | 22 (28.2) | 0.313 |
| Hyperlipidemia, n (%) | 17 (37.8) | 22 (28.2) | 0.272 |
| Chronic obstructive pulmonary disease, n (%) | 3 (6.7) | 10 (12.8) | 0.370 |
| Prior hospitalization for heart failure, n (%) | 34 (75.6) | 48 (61.5) | 0.112 |
| Chronic kidney disease, n (%) | 15 (33.3) | 23 (29.5) | 0.657 |
| Hyperuricemia, n (%) | 11 (24.4) | 18 (23.1) | 0.863 |
| History of malignancy, n (%) | 3 (6.7) | 4 (5.1) | 0.706 |
| History of depression, n (%) | 3 (6.7) | 3 (3.8) | 0.668 |
| Laboratory tests | |||
| Estimated GFR (ml/min/1.73 m2) | 63.8 ± 27.5 | 60.5 ± 26.3 | 0.513 |
| Hemoglobin (g/dL) | 13.0 ± 2.1 | 13.0 ± 2.1 | 0.963 |
| Alanine aminotransferase (IU/L) | 26.8 ± 36.3 | 38.0 ± 90.6 | 0.441 |
| Low-density lipoprotein (mg/dL) | 111.0 ± 39.3 | 107.3 ± 38.1 | 0.634 |
GFR, glomerular filtration rate.
Medications for heart failure
Table 2 shows the prescription rates and dosages of HF medications. The prescription rate of RASis [including angiotensin converting enzyme inhibitors (ACEis), angiotensin receptor blockers (ARBs), or sacubitril/valsartan] was 84.6% following CRT implantation and 88.6% at the end of follow-up, respectively. The prescription rate of sacubitril/valsartan increased from 29.3% following CRT implantation to 55.3% at the end of follow-up (p < 0.001). The prescription rate of beta-blockers was 74.8% following CRT implantation and 82.1% at the end of follow-up. The prescription rate of mineralocorticoid receptor antagonists (MRAs) was 63.4% following CRT implantation and 65.9% at the end of follow-up, respectively. The prescription rate of RASis (including ACEis, ARBs, or sacubitril/valsartan), beta-blockers, mineralocorticoid receptor antagonist (MRAs), and digoxin were comparable between Group 1 and Group 2 during the study period.
Table 2. Heart failure medications during the study period.
| Ivabradine, Gr I (n = 45) | Non-ivabradine, Gr II (n = 78) | p value | |
| Post-CRT implantation | |||
| RASi (ACEi, ARB or Sac/Val), n (%) | 36 (80.0) | 68 (87.2) | 0.289 |
| ≥ 50% target dose, n (% RASi used) | 13 (36.1) | 35 (51.5) | 0.135 |
| ACEi or ARB, n (%) | 16 (35.6) | 52 (66.7) | < 0.001 |
| ≥ 50% target dose, n (% ACEi/ARB used) | 7 (43.8) | 28 (53.8) | 0.480 |
| Sac/Val, n (%) | 20 (44.4) | 16 (20.5) | 0.005 |
| ≥ 50% target dose, n (% Sac/Val used) | 6 (30.0) | 7 (43.8) | 0.393 |
| Beta-blocker, n (%) | 33 (73.3) | 59 (75.6) | 0.776 |
| ≥ 50% target dose, n (% Beta-blocker used) | 18 (54.5) | 33 (55.9) | 0.898 |
| MRA, n (%) | 29 (64.4) | 49 (62.8) | 0.857 |
| ≥ 50% target dose, n (% MRA used) | 25 (86.2) | 41 (83.7) | 0.764 |
| Digoxin, n (%) | 11 (24.4) | 24 (30.8) | 0.454 |
| At the end of the follow-up | |||
| Ivabradine, n (%) | 44 (97.8) | 0 (0.0) | < 0.001 |
| RASi (ACEi, ARB or Sac/Val), n (%) | 40 (88.9) | 69 (88.5) | 0.943 |
| ≥ 50% target dose, n (% RASi used) | 24 (60.0) | 33 (47.8) | 0.170 |
| ACEi or ARB, n (%) | 11 (24.4) | 30 (38.5) | 0.112 |
| ≥ 50% target dose, n (% ACEi/ARB used) | 3 (27.3) | 12 (40.0) | 0.716 |
| Sac/Val, n (%) | 29 (64.4) | 39 (50.0) | 0.121 |
| ≥ 50% target dose, n (% Sac/Val used) | 21 (72.4) | 21 (53.8) | 0.119 |
| Beta-blocker, n (%) | 38 (84.4) | 63 (80.8) | 0.608 |
| ≥ 50% target dose, n (% Beta-blocker used) | 21 (55.3) | 34 (54.0) | 0.902 |
| MRA, n (%) | 33 (73.3) | 48 (61.5) | 0.184 |
| ≥ 50% target dose, n (% MRA used) | 28 (84.8) | 40 (83.3) | 0.872 |
| Digoxin, n (%) | 5 (11.1) | 18 (23.1) | 0.101 |
ACEi, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker; CRT, cardiac resynchronization therapy; MRA, mineralocorticoid receptor antagonist; RASi, renin angiotensin system inhibitor; Sac/Val, sacubitril/valsartan.
Ivabradine was initiated in 45 CRT recipients with a mean daily dose of 7.4 ± 2.4 mg. Ivabradine was well-tolerated and was discontinued in one patient due to permanent AF.
Vital signs, echocardiographic data, CRT parameters, and re-admission for HF
Table 3 demonstrates the changes in vital signs and echocardiographic parameters during the study period. After successful CRT implantation, mean QRS duration shortened to 148.2 ± 21.6 msec (p < 0.001), and mean LVEF increased to 30.3 ± 7.6% (p < 0.001). There were no significant changes in systolic blood pressure and heart rate before and after CRT implantation.
Table 3. Alternations of vital signs and echocardiographic parameters following treatments.
| Ivabradine, Gr I (n = 45) | Non-ivabradine, Gr II (n = 78) | p value | |
| Pre-CRT implantation | |||
| Systolic BP (mmHg) | 118.1 ± 14.3 | 115.9 ± 18.6 | 0.457 |
| Heart rate (bpm) | 85.6 ± 14.7 | 80.6 ± 16.2 | 0.093 |
| QRS duration (msec) | 162.1 ± 25.5 | 162.4 ± 18.6 | 0.947 |
| NYHA functional class | 3.3 ± 0.5 | 3.2 ± 0.5 | 0.263 |
| LVEF (%) | 23.1 ± 5.2 | 24.9 ± 6.5 | 0.104 |
| LA (mm) | 50.0 ± 8.3 | 50.2 ± 6.2 | 0.875 |
| LVEDD (mm) | 65.2 ± 11.6 | 63.2 ± 7.6 | 0.314 |
| LVESD (mm) | 54.9 ± 12.5 | 52.4 ± 9.5 | 0.247 |
| PASP (mmHg) | 38.1 ± 17.8 | 39.8 ± 13.3 | 0.544 |
| Post-CRT implantation | |||
| Systolic BP (mmHg) | 120.5 ± 15.6 | 119.6 ± 19.4 | 0.808 |
| Heart rate (bpm) | 82.2 ± 11.4 | 78.9 ± 10.6 | 0.112 |
| QRS duration (msec) | 147.4 ± 20.3 | 148.7 ± 22.5 | 0.770 |
| NYHA functional class | 2.7 ± 0.5 | 2.6 ± 0.7 | 0.686 |
| LVEF (%) | 29.9 ± 6.5 | 30.5 ± 8.2 | 0.717 |
| LA (mm) | 49.3 ± 8.9 | 47.5 ± 6.7 | 0.199 |
| LVEDD (mm) | 61.3 ± 11.9 | 60.0 ± 9.3 | 0.499 |
| LVESD (mm) | 49.1 ± 12.0 | 47.7 ± 12.0 | 0.529 |
| PASP (mmHg) | 30.9 ± 10.7 | 34.0 ± 12.2 | 0.142 |
| At the end of the follow-up | |||
| Systolic BP (mmHg) | 118.2 ± 17.1 | 119.0 ± 19.2 | 0.770 |
| Heart rate (bpm) | 76.3 ± 10.5 | 79.7 ± 10.3 | 0.272 |
| Δ Heart rate (bpm) | -5.9 ± 13.6 | 0.8 ± 9.9 | 0.002 |
| NYHA functional class | 2.4 ± 0.7 | 2.5 ± 0.8 | 0.548 |
| LVEF (%) | 38.8 ± 12.4 | 36.0 ± 12.0 | 0.236 |
| Δ LVEF (%) | 8.9 ± 11.4 | 5.6 ± 8.8 | 0.076 |
| LA (mm) | 46.4 ± 7.5 | 47.3 ± 5.7 | 0.481 |
| LVEDD (mm) | 54.7 ± 16.4 | 56.4 ± 9.6 | 0.536 |
| LVESD (mm) | 42.8 ± 16.8 | 44.1 ± 12.6 | 0.625 |
| PASP (mmHg) | 31.6 ± 10.7 | 35.4 ± 11.9 | 0.084 |
BP, blood pressure; LA, left atrium; LVEDD, left ventricular end-diastolic diameter; LVEF, left ventricular ejection fraction; LVESD, left ventricular end-systolic diameter; NYHA, New York Heart Association; PASP, pulmonary arterial systolic pressure.
In Group 1, the mean heart rate decreased from 82.2 ± 11.4 bpm to 76.3 ± 10.5 bpm (p = 0.012) following ivabradine treatment. The decrease in heart rate was significantly greater in Group 1 than in Group 2 (Δ Heart rate -5.9 ± 13.6 bpm vs. 0.8 ± 9.9 bpm, p = 0.002). Mean LVEF increased in both groups during the study period. In Group 1, LVEF improved from 29.9 ± 6.5% to 38.8 ± 12.4% (p < 0.001) following ivabradine treatment. The improvement in LVEF was numerically greater in Group 1 than in Group 2, but the difference was not statistically significant (Δ LVEF 8.9 ± 11.4% vs. 5.6 ± 8.8%, p = 0.076).
Changes in CRT parameters during the study period are shown in Table 4 and Figure 2. In Group 1, there were no significant differences in biventricular pacing percentage and AF burden before and after ivabradine treatment. There was a trend of an increase in atrial pacing percentage following ivabradine treatment, but it was not statistically significant. The patients’ daily activities significantly increased from 2.4 ± 1.4 hours/day to 2.8 ± 1.6 hours/day following ivabradine treatment (p < 0.001). One patient in Group 1 and five patients in Group 2 developed permanent AF during the study period. The burden of AF did not reach statistical significance between the two groups (Group II vs. Group I: 6.7 ± 23.9% vs. -0.5 ± 17.3%, p = 0.058), and the increase in daily activities was significantly greater in Group 1 than in Group 2 (0.4 ± 0.7 hours/day vs. -0.1 ± 7.2 hours/day, p < 0.001). There were no significant differences in LVEF improvement, atrial pacing percentage, burden of AF and daily activities between the patients with device algorithm-based and ECG/echocardiography-based programming.
Table 4. Alternations of CRT parameters following treatments.
| Ivabradine, Gr I (n = 45) | Non-ivabradine, Gr II (n = 78) | p value | |
| Post-CRT implantation | |||
| Atrial pacing percentage (%) | 3.8 ± 6.5 | 6.6 ± 10.3 | 0.067 |
| Atrial fibrillation burden (%) | 3.4 ± 12.5 | 2.5 ± 11.7 | 0.711 |
| Bi-V pacing percentage (%) | 97.7 ± 3.7 | 97.8 ± 4.1 | 0.865 |
| Daily activity (hour/day) | 2.4 ± 1.4 | 2.4 ± 2.1 | 0.998 |
| At the end of the follow-up | |||
| Atrial pacing percentage (%) | 7.0 ± 9.5 | 8.6 ± 13.9 | 0.479 |
| Atrial fibrillation burden (%) | 2.9 ± 14.3 | 9.2 ± 27.2 | 0.093 |
| Δ Atrial fibrillation burden (%) | -0.5 ± 17.3 | 6.7 ± 23.9 | 0.058 |
| Progress to permanent atrial fibrillation | 1 (2.2) | 5 (6.4) | 0.414 |
| Bi-V pacing percentage (%) | 98.0 ± 3.8 | 97.4 ± 4.2 | 0.438 |
| Daily activity (hour/day) | 2.8 ± 1.6 | 2.3 ± 2.1 | 0.140 |
| Δ Daily activity (hour/day) | 0.4 ± 0.7 | -0.1 ± 7.2 | < 0.001 |
Bi-V, bi-ventricular; CRT, cardiac resynchronization therapy; LA, left atrium; LVEDD, left ventricular end diastolic diameter; LVEF, left ventricular ejection fraction; LVESD, left ventricular end systolic diameter; PASP, pulmonary arterial systolic pressure.
Figure 2.
Distribution of atrial pacing percentage (A), atrial fibrillation burden (B), biventricular pacing percentage (C), and patients’ daily activities (D) before and after ivabradine treatment.
The mean follow-up duration was 1192 ± 362 days, and there was no significant difference between the two groups (1211 ± 369 days vs. 1181 ± 360 days, p = 0.660). The overall incidence of first unplanned HF re-admission was 10.99% per patient-year. Kaplan-Meier survival curves (Figure 3) showed a similar risk of HF re-admission in the CRT recipients with and without ivabradine treatment (8.06% per patient-year vs. 12.85% per patient-year, p = 0.273). The overall incidence of all-cause mortality was 3.24% per patient-year. The risks of morality in the patients with and without ivabradine treatment were similar (2.68% per patient-year vs. 3.57% per patient-year, p = 0.603).
Figure 3.
Kaplan-Meier curves of the first unplanned heart failure re-hospitalization in the patients with and without ivabradine treatment.
DISCUSSION
In symptomatic HF patients with a QRS duration ≥ 120 msec and depressed LV systolic function, CRT therapy has been shown to improve LV function and reduce LV volume.12,13 However, not all patients equally benefit from CRT therapy. It is useful to assess LV reverse remodeling following CRT implantation since impaired contractility is the central pathophysiology underlying HF syndrome, and patients who fail to improve from baseline LV systolic dysfunction following CRT implantation warrant careful and optimal HF management.
Underutilization of guideline-directed medical therapy is a major issue of HF care in real-world practice. A French National Database study demonstrated that the prescription of guideline-recommended medical therapy was suboptimal in HF patients with CRT or implantable cardioverter defibrillator, and that the non-optimized patient group had a significantly higher HF hospitalization rate than those with medical optimization.14 Patients with CRT usually have a higher risk and more comorbidities than general HF patients, and the utilization of guideline-recommended medications is often limited in CRT recipients.15 Two previous hospital-based HF registries demonstrated low prescription rates of RASis and beta-blockers (both 60-70%) among Taiwanese HFrEF patients.16,17 Moreover, suboptimal adherence to guideline-directed therapy has been associated with adverse clinical outcomes.16 In the current study, although the prescription rates of RASis (including ACEis, ARBs, or sacubitril/valsartan), and beta-blockers were slightly higher (75-85%) than those in the aforementioned registries, the doses of these therapies remained significantly lower than in clinical trials.
Hypotension and bradycardia are important barriers for initiating and titrating guideline-recommended therapies. CRT improves hemodynamics, prevents bradycardia, and allows up-titration of RASis and beta-blockers.18-20 Ivabradine is currently recommended in HFrEF patients with a sinus rate ≥ 70 bpm.2,3 The specific mechanism of ivabradine allows it to reduce heart rate without inducing hypotension. Moreover, ivabradine has been associated with an increase in directly measured central systolic pressure, and may more easily allow the initiation or up-titration of beta-blocker dose.21,22 However, its effect on CRT recipients has seldom been reported.
Both CRT and ivabradine have been shown to be beneficial for left ventricular reverse structural remodeling. In the MIRACLE study, the mean improvements in LVEF from baseline were 5.2% and 7.2% at 6 months and 12 months, respectively, following CRT implantation.23 Ivabradine treatment also showed a modest but significant increase in LVEF in two randomized trials (2.0 ± 7.0% in the BEAUTIFUL study and 2.4 ± 7.7% in the SHIFT study).24,25 Similarly, subsequent improvements in LVEF and decreases in left ventricular size were noted following CRT and ivabradine treatment in the current study.
In addition to LVEF improvement, ivabradine has been shown to improve peak oxygen consumption, exercise tolerance, and 6-minute walking distance.26-28 Ates et al. reported significant improvements in life quality score and 6-minute walking distance following 3 months of ivabradine treatment in a single-arm study consisting of 29 patients with a previously implanted CRT-defibrillator.28 The current study assessed patients’ functional capacity according to CRT-calculated daily activity parameters, which again demonstrated a significant increase in activity time following ivabradine treatment in CRT recipients compared to conventional HF treatment. Functional capacity is an essential therapeutic goal in HF therapy, and ivabradine seems to provide an additional benefit compared with other non-ivabradine based standard treatments.29-31
Ivabradine may affect the electrical properties of pulmonary venous myocytes and increase the risk of AF.32 However, although the risk of AF was higher in the ivabradine arm than in the placebo arm in the SHIFT sub-analysis (4.8% vs. 4.2% per patient-year, respectively), the risks of ischemic stroke and worsening HF were lower in the ivabradine arm (0.6% and 14.4% per patient-year, respectively) than in the placebo arm (0.9% and 17.7% per patient-year, respectively), indicating that a higher incidence of AF following ivabradine treatment did not confer a higher risk of severe AF-related adverse events.33,34 In CRT recipients, AF is a common cause of loss of cardiac synchronization. In a retrospective analysis, 11.5% of CRT recipients had a < 90% bi-ventricular stimulation, and atrial tachyarrhythmias occurred in > 50% of the patients.9 In the current study, we found that in the patients not treated with ivabradine, the risk of developing permanent AF, the percentage of AF burden and the bi-ventricular pacing percentage were similar to those who were treated with ivabradine. Moreover, although AF may be underdiagnosed in the general population, the presence of atrial lead in CRT recipients can assist in the detection of asymptomatic AF and facilitate a timely response to minimize AF-associated complications. The findings of the current study suggest that ivabradine can be safely prescribed in CRT recipients.
This study had several limitations. First, according to the inclusion and exclusion criteria, the patient population was highly selected, and therefore the results may not be generalizable to other HFrEF patients. Moreover, the number of patients may be too small to achieve statistical power. Second, although natriuretic peptide levels and left ventricular end-systolic volume index are useful to evaluate changes in the clinical course of HF, these measurements were not widely available during the study period. Third, the prescription rates of other guideline-directed HF medications such as sacubitril/valsartan and MRAs were not consistent during the follow-up period. Hence, it is challenging to conclude that the improvement in functional status in the ivabradine group was purely due to its benefit. Fourth, we did not analyze the positions of CRT leads in this study.
CONCLUSIONS
Among the patients who received CRT therapy but who still had a LVEF < 40% and resting sinus rate ≥ 75 bpm, ivabradine treatment effectively reduced the heart rate and enhanced their physical activity. Furthermore, ivabradine treatment was well-tolerated and did not increase AF burden or affect biventricular pacing percentage in the HF patients.
Acknowledgments
We are grateful to Ms. Hsiao-Jen Chen and Mr. Tzu-Yuan Sung for their effort in data collection.
FUNDING
This work was supported by Cheng Hsin General Hospital [CHGH106-10, CHGH108-15, CHGH109-(IP) 1-01, CHGH109-(IP)1-02] and Taichung Veterans General Hospital, Taichung, Taiwan [Project Number: TCVGH-1093103C, TCVGH-1083104C, and TCVGH-107 3104C].
DECLARATION OF CONFLICT OF INTEREST
All the authors declare no conflict of interest.
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