DOI: https://doi.org/10.21203/rs.3.rs-2881917/v1
To investigate the efficacy of early use of ivabradine in patients with acute myocardial infarction (AMI) after percutaneous coronary intervention (PCI).
Eighty patients with AMI were randomly divided into the ivabradine group and the control group. The ivabradine group was treated with ivabradine combined with metoprolol after PCI, while the control group was treated with metoprolol only. Both groups were treated continuously for 1 year. Echocardiography-derived parameters, heart rate, cardiopulmonary exercise testing (CPET) data, major adverse cardiac events (MACE) and myocardial markers were analyzed.
The echocardiography-derived left ventricular ejection fraction was significantly higher in the ivabradine group than in the control group at 1 week, 3 months and 1 year after PCI. The heart rate of the ivabradine group was significantly lower than that of the control group at 1 week after PCI. The VO2max, metabolic equivalents, anaerobic threshold heart rate, peak heart rate, and heart rate recovery at 8 minutes of the ivabradine group were significantly higher than those of the control group at 1 year after PCI. The one-year total incidence of major adverse cardiac events was 10% in the ivabradine group, which was significantly lower than the 37.5% in the control group. The B-type natriuretic peptide of the ivabradine group was significantly lower than that of the control group on Day 2 and Day 3 after PCI. The troponin I level of the ivabradine group was significantly lower than that of the control group on Day 5 after PCI.
Early use of ivabradine in patients with AMI after PCI can achieve effective heart rate control, reduce myocardial injury, improve cardiac function and exercise tolerance, and reduce the incidence of major adverse cardiac events.
Acute myocardial infarction (AMI) is a cardiovascular disease that seriously threatens human health and safety and is characterized by rapid disease progression, serious complications and high mortality [1]. Timely and effective revascularization is a critical means of saving the lives of AMI patients, but some patients still have decreased left ventricular systolic function, which leads to heart failure [2]. AMI patients need to optimize drug treatment after percutaneous coronary intervention (PCI) to further improve cardiac function and reduce cardiovascular mortality. Heart rate control is an important measure to improve the long-term prognosis of AMI patients [3]. β-receptor blockers are the most commonly used drugs to control heart rate, which can reduce myocardial infarction area, attenuate myocardial inflammation, and inhibit cardiac remodeling [4]. However, their application is greatly limited by negative conduction and negative inotropic effects. Ivabradine is the first specific inhibitor of If current in the sinoatrial node, which can simply slow heart rate and have no adverse effects on myocardial contractility and cardiac conduction [5]. Previous studies have shown that ivabradine has a good effect in patients with heart failure and stable coronary artery disease [6, 7], but its therapeutic effect in acute myocardial infarction is not clear. The aim of this study is to investigate the efficacy of early use of ivabradine in patients with acute myocardial infarction after PCI and to provide new ideas for the treatment of myocardial infarction.
Patients with acute myocardial infarction who were hospitalized from February 2020 to May 2021 were selected. The study was approved by Ethics Committee of Putuo Central Hospital. The patients provided their written informed consent to participate in this study.
The inclusion criteria were as follows: 1. all patients met the diagnostic criteria of acute myocardial infarction and successfully underwent emergency PCI; 2. sinus rhythm and heart rate ≥ 75 beats/min; and 3. age between 18 and 85 years old.
The exclusion criteria were as follows: 1. a history of bronchial asthma; 2. a history of bradyarrhythmia; 3. systolic blood pressure ≤ 90 mmHg; and 4. vasoactive drugs were still used for shock 6 hours after PCI.
This study is a prospective, single-center, randomized controlled registration study (registration number: ChiCTR2000032731). The study design is shown in Fig. 1.
All patients received a loading dose of 300 mg aspirin and 180 mg ticagrelor (or 300 mg clopidogrel) before PCI. During the operation, a IIb/IIIa receptor antagonist, temporary pacemaker implantation, and intra-aortic balloon pump were applied according to the condition. All patients were routinely treated with antiplatelet agents, low molecular weight heparin, statins, angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs) or angiotensin receptor neprilysin inhibitors (ARNIs) after the operation. At 12 hours after PCI, the ivabradine group was treated with ivabradine (5 mg twice a day) combined with metoprolol tartrate (12.5 mg twice a day), while the control group was treated with metoprolol tartrate (12.5 mg twice a day) only. On Day 3 after PCI, metoprolol tartrate was replaced with long-acting metoprolol succinate (metoprolol sustained-release tablets), and the dose of β-blockers was titrated according to the 2017 Guidelines for the Diagnosis and Treatment of Acute Myocardial Infarction [8], as shown in Table 1. At the same time, the drug dose of the two groups was adjusted individually according to the individual’s heart rate, and the target heart rate was set at 70 beats/min. If bradycardia (heart rate < 50 beats/min) occurred during the treatment, drug administration was stopped, and the trial was terminated.
| Time point | β-receptor blocker | Ivabradine |
|---|---|---|
| metoprolol tartrate | / | |
| 1 day after PCI | 12.5mg, bid | 5mg, bid |
| 2 days after PCI | 12.5mg, bid | 5mg, bid |
| metoprolol succinate | / | |
| 3 days after PCI | 23.75mg, qd | 5mg, bid |
| 1 week after PCI | 47.5mg, qd | 5mg, bid |
| 2 weeks after PCI | 95mg, qd | 5mg, bid |
| 4 weeks after PCI | 142.5mg, qd | 5mg, bid |
| 8 weeks after PCI | 190mg, qd | 5mg, bid |
| Notes: 1. In case of heart failure, bronchial asthma and other clinical conditions, the dose of β-blockers should be maintained or reduced according to the conditions. 2. Heart rate and blood pressure were evaluated every day during hospitalization to determine whether the dose of β-blockers needed to be increased or decreased. If the conditions were met, the dose was increased gradually according to the time point in the table. 3. Ivabradine was discontinued if photosensitive reaction occurred. | ||
A color Doppler ultrasound diagnostic instrument was used to perform echocardiography in the two groups of patients. The left ventricular ejection fraction (LVEF), left ventricular end-systolic internal diameter (LVIDs), left ventricular end-diastolic internal diameter (LVIDd), left atrial diameter (LAD), interventricular septal thickness (IVST) and E/e' ratio were recorded at baseline and after treatment (1 week, 3 months, and 1 year after PCI). The heart rate and blood pressure of the two groups were recorded at baseline and after treatment (1 week, 3 months, and 1 year after PCI). The two groups of patients underwent CPET one year after PCI. The maximal oxygen uptake (VO2max), metabolic equivalents (METs), resting heart rate, anaerobic threshold (AT) heart rate, peak heart rate, 8-minute heart rate, heart rate recovery at 8 minutes (HRR8), resting blood pressure, AT blood pressure, and peak blood pressure were recorded. Major adverse cardiac events (MACE), including cardiac death, heart failure, recurrent angina, and recurrent myocardial infarction, were recorded at the one-year follow-up. The levels of B-type natriuretic peptide (BNP), troponin I (TnI) and creatine kinase-MB (CK-MB) in the two groups were determined before PCI, 2 hours after PCI, and daily for 6 days after PCI. The levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine, urea nitrogen and uric acid in the two groups were determined at baseline and 1 year after PCI.
SPSS 25.0 statistical software was used for data processing. Measurement data with a normal distribution are expressed as the mean ± standard deviation ( ±s), and Student´s t test was used for comparisons between groups. Measurement data with a nonnormal distribution are expressed as the median (interquartile range, IQR), and the Wilcoxon rank sum test was used for comparisons between groups. Count data are expressed as frequencies (percentages, %), and the chi-square test or Fisher’s exact probability method was used for comparisons between groups. P < 0.05 indicated that the difference was statistically significant.
According to the inclusion and exclusion criteria, a total of 80 patients were randomized in this study, including 40 patients in the ivabradine group and 40 patients in the control group, as shown in Fig. 2. There were no significant differences in the general clinical conditions and coronary artery lesions at baseline between the two groups (P > 0.05) (Table 2).
| Items | Ivabradine group (40 cases) | Control group (40 cases) | P value |
|---|---|---|---|
| Age (Mean ± SD, year) | 68.53 ± 10.21 | 67.4 ± 11.44 | 0.651 |
| Male [n (%)] | 30(75.00) | 33(82.50) | 0.412 |
| Complication [n (%)] | |||
| Hypertension | 20(50.00) | 24(60.00) | 0.369 |
| Diabetes mellitus | 14(35.00) | 10(25.00) | 0.329 |
| Hyperlipidemia | 15(37.50) | 11(27.50) | 0.340 |
| STEMI [n (%)] | 23(57.50) | 28(70.00) | 0.245 |
| Number of diseased vessels [n (%)] | 0.073 | ||
| 1 | 14(35.00) | 8(20.00) | |
| 2 | 12(30.00) | 22(55.00) | |
| 3 | 14(35.00) | 10(25.00) | |
| Infarct-related artery [n (%)] | 0.204 | ||
| LAD | 24(60.00) | 25(62.50) | |
| LCX | 6(15.00) | 2(5.00) | |
| RCA | 10(25.00) | 10(25.00) | |
| Others | 0(0.00) | 3(7.50) | |
| ALT [median (IQR), U/L)] | 40.00(25.50,56.75) | 40.00(28.25,87.25) | 0.722 |
| AST [median (IQR), U/L)] | 142.00(54.75,236.00) | 163.00(81.00,377.00) | 0.324 |
| Creatinine [median (IQR), µmol/L)] | 70.50(60.00,84.75) | 69.50(59.50,83.25) | 0.855 |
| Urea nitrogen [median (IQR), mmol/L)] | 5.65(4.53,7.63) | 6.25(4.60,7.68) | 0.600 |
| Uric acid [median (IQR), µmol/L)] | 336.00(286.75,415.75) | 390.00(305.75,460.50) | 0.082 |
| Total cholesterol (Mean ± SD, mmol/L) | 5.28 ± 1.29 | 5.21 ± 1.29 | 0.784 |
| Triglyceride [median (IQR), mmol/L)] | 1.35(1.05,2.09) | 1.26(0.89,1.93) | 0.324 |
| LDL cholesterol (Mean ± SD, mmol/L) | 3.63 ± 0.98 | 3.63 ± 1.04 | 0.989 |
| HDL cholesterol (Mean ± SD, mmol/L) | 1.16 ± 0.20 | 1.11 ± 0.26 | 0.365 |
| ACEI/ARB/ARNI [n (%)] | 32(80.00) | 31(77.50) | 0.785 |
| Beta blocker [n (%)] | 40(100.00) | 40(100.00) | 1.000 |
| Aldosterone receptor antagonist [n (%)] | 8(20.00) | 6(15.00) | 0.556 |
| STEMI ST-segment elevation myocardial infarction, LAD left anterior descending artery, LCX left circumflex artery, RCA right coronary artery, ALT alanine aminotransferase, AST aspartate aminotransferase, LDL low density lipoprotein, HDL high density lipoprotein, ACEI angiotensin-converting enzyme inhibitor, ARB angiotensin receptor blocker, ARNI angiotensin receptor neprilysin inhibitor | |||
There was no significant difference in LVEF between the two groups before treatment (P > 0.05). The LVEF of the ivabradine group was significantly higher than that of the control group at 1 week, 3 months and 1 year after PCI (P < 0.05). There was no significant difference in LAD between the two groups before treatment (P > 0.05). The LAD of the ivabradine group was significantly lower than that of the control group at 1 week after PCI (P < 0.05), but there was no significant difference in LAD between the two groups at 3 months and 1 year after PCI (P > 0.05). There were no significant differences in LVIDs, LVIDs, IVST and E/e' ratio between the two groups before and after treatment (P > 0.05) (Table 3).
| Items | Ivabradine group (40 cases) | Control group (40 cases) | P value |
|---|---|---|---|
| LVEF (%) | |||
| Baseline level | 52.05 ± 7.42 | 50.08 ± 9.05 | 0.623 |
| 7 days later | 57.00 ± 7.87 | 50.70 ± 10.79 | 0.042 |
| 3 months later | 56.57 ± 9.99 | 50.97 ± 10.30 | 0.023 |
| 12 months later | 59.32 ± 8.11 | 51.94 ± 11.75 | 0.006 |
| LVIDs (mm) | |||
| Baseline level | 33.88 ± 5.60 | 34.15 ± 5.86 | 0.493 |
| 7 days later | 32.20 ± 5.49 | 34.85 ± 5.91 | 0.101 |
| 3 months later | 32.93 ± 6.39 | 35.42 ± 6.56 | 0.070 |
| 12 months later | 33.74 ± 6.63 | 36.38 ± 7.81 | 0.149 |
| LVIDd (mm) | |||
| Baseline level | 47.35 ± 5.10 | 48.43 ± 5.67 | 0.375 |
| 7 days later | 48.20 ± 5.60 | 50.60 ± 5.37 | 0.175 |
| 3 months later | 48.82 ± 7.18 | 49.76 ± 5.04 | 0.357 |
| 12 months later | 49.39 ± 5.91 | 50.76 ± 6.42 | 0.373 |
| LAD (mm) | |||
| Baseline level | 37.90 ± 3.78 | 38.00 ± 3.40 | 0.739 |
| 7 days later | 37.30 ± 3.13 | 39.50 ± 2.78 | 0.024 |
| 3 months later | 36.96 ± 4.69 | 38.06 ± 5.04 | 0.385 |
| 12 months later | 37.55 ± 3.02 | 37.97 ± 3.93 | 0.721 |
| IVST (mm) | |||
| Baseline level | 10.72 ± 1.19 | 10.77 ± 1.21 | 0.911 |
| 7 days later | 10.40 ± 1.39 | 10.95 ± 1.28 | 0.098 |
| 3 months later | 9.82 ± 1.36 | 10.42 ± 1.42 | 0.080 |
| 12 months later | 10.00 ± 1.34 | 10.18 ± 2.11 | 0.721 |
| E/e’ | |||
| Baseline level | 11.80 ± 4.26 | 11.17 ± 3.00 | 0.832 |
| 7 days later | 10.86 ± 3.03 | 12.42 ± 3.18 | 0.124 |
| 3 months later | 11.01 ± 5.13 | 10.26 ± 3.39 | 0.592 |
| 12 months later | 10.32 ± 2.32 | 10.06 ± 2.72 | 0.441 |
| LVEF left ventricular ejection fraction, LVIDs left ventricular end-systolic internal diameter, LVIDd | |||
| left ventricular end-diastolic internal diameter, LAD left atrial diameter, IVST interventricular septal thickness | |||
There was no significant difference in heart rate between the two groups before treatment (P > 0.05). The heart rate of the ivabradine group was significantly lower than that of the control group at 1 week after PCI (P < 0.05). There was no significant difference in heart rate between the two groups at 3 months and 1 year after PCI (P > 0.05). There was no significant difference in blood pressure between the two groups before and after treatment (P > 0.05) (Table 4).
| Items | Ivabradine group (40 cases) | Control group (40 cases) | P value |
|---|---|---|---|
| Heart rate (bpm) | |||
| Baseline level | 90.00 ± 8.80 | 87.95 ± 9.66 | 0.212 |
| 7 days later | 73.20 ± 4.54 | 76.95 ± 5.87 | 0.010 |
| 3 months later | 65.38 ± 4.06 | 66.83 ± 4.40 | 0.142 |
| 12 months later | 65.50 ± 3.34 | 65.83 ± 3.18 | 0.657 |
| Systolic pressure (mmHg) | |||
| Baseline level | 135.23 ± 22.05 | 128.43 ± 19.55 | 0.148 |
| 7 days later | 130.23 ± 12.98 | 124.83 ± 13.18 | 0.069 |
| 3 months later | 130.20 ± 8.32 | 126.45 ± 9.54 | 0.065 |
| 12 months later | 130.50 ± 11.63 | 127.35 ± 17.43 | 0.450 |
| Diastolic pressure (mmHg) | |||
| Baseline level | 77.65 ± 12.56 | 75.20 ± 9.00 | 0.319 |
| 7 days later | 76.00 ± 7.85 | 73.03 ± 6.56 | 0.070 |
| 3 months later | 75.55 ± 5.55 | 74.23 ± 4.90 | 0.261 |
| 12 months later | 75.71 ± 8.71 | 74.77 ± 10.22 | 0.722 |
The VO2max, METs, AT heart rate, peak heart rate and HRR8 in the ivabradine group were significantly higher than those in the control group at 1 year after PCI (P < 0.05). There were no significant differences in resting heart rate, 8-minute heart rate, resting blood pressure, AT blood pressure or peak blood pressure between the two groups (P > 0.05) (Table 5).
| Items | Ivabradine group (40 cases) | Control group (40 cases) | P value |
|---|---|---|---|
| VO2max [ml/(min·kg)] | 22.41 ± 4.74 | 20.19 ± 4.54 | 0.048 |
| METs | 6.41 ± 1.36 | 5.76 ± 1.30 | 0.022 |
| Resting heart rate (bpm) | 77.78 ± 10.06 | 74.08 ± 8.95 | 0.086 |
| AT heart rate (bpm) | 107.90 ± 14.51 | 101.70 ± 11.22 | 0.036 |
| Peak heart rate (bpm) | 135.03 ± 18.30 | 124.88 ± 16.33 | 0.011 |
| 8-minute heart rate (bpm) | 79.40 ± 9.53 | 83.10 ± 7.79 | 0.061 |
| HRR8 (bpm) | 55.63 ± 15.99 | 41.78 ± 15.19 | 0.000 |
| Resting systolic pressure (mmHg) | 119.15 ± 16.74 | 123.13 ± 16.31 | 0.285 |
| Resting diastolic pressure (mmHg) | 79.53 ± 13.58 | 77.93 ± 9.52 | 0.544 |
| AT systolic pressure (mmHg) | 139.55 ± 22.60 | 139.20 ± 20.59 | 0.942 |
| AT diastolic pressure (mmHg) | 77.28 ± 13.82 | 76.13 ± 10.41 | 0.675 |
| Peak systolic pressure (mmHg) | 158.10 ± 23.43 | 157.25 ± 22.73 | 0.870 |
| Peak diastolic pressure (mmHg) | 81.23 ± 15.25 | 75.73 ± 11.26 | 0.070 |
| CPET cardiopulmonary exercise testing, VO2max maximum oxygen uptake, METs metabolic equivalents, AT anaerobic threshold | |||
All patients were followed up for 1 year. The total incidence of cardiac death, heart failure, recurrent angina, and recurrent myocardial infarction was 10% in the ivabradine group, which was lower than the 37.5% in the control group, and the difference was statistically significant (P < 0.01) (Table 6).
| Items | Ivabradine group (40 cases) | Control group (40 cases) | P value |
|---|---|---|---|
| Cardiogenic death [n (%)] | 0(0.00) | 0(0.00) | 1.000 |
| Heart failure [n (%)] | 0(0.00) | 5(12.50) | 0.065 |
| Recurrent angina [n (%)] | 3(7.50) | 9(22.50) | 0.060 |
| Reinfarction [n (%)] | 1(2.50) | 1(2.50) | 1.000 |
| MACE [n (%)] | 4(10.00) | 15(37.50) | 0.004 |
| MACE major adverse cardiac events | |||
The BNP of the ivabradine group was significantly lower than that of the control group on Day 2 and Day 3 after PCI (P < 0.05) (Fig. 3a). The TnI of the ivabradine group was significantly lower than that of the control group on Day 5 after PCI (P < 0.05) (Fig. 3b). There was no significant difference in CK-MB between the two groups (P > 0.05) (Fig. 3c).
There were no significant differences in ACEI/ARB/ARNI, β-blocker, aldosterone receptor antagonist, loop diuretic, and dual antiplatelet medications between the two groups at baseline and at the one-year follow-up (P > 0.05) (Table 7).
| Items | Ivabradine group (40 cases) | Control group (40 cases) | P value |
|---|---|---|---|
| Medication at baseline | |||
| ACEI/ARB/ARNI | 32(80.00) | 31(77.50) | 0.785 |
| Maximum tolerable/standard dose [n (%)] | 26(65.00) | 28(70.00) | 0.633 |
| Beta blocker | 40(100.00) | 40(100.00) | 1.000 |
| Maximum tolerable/standard dose [n (%)] | 25(62.50) | 20(50.00) | 0.260 |
| Aldosterone receptor antagonist [n (%)] | 8(20.00) | 6(15.00) | 0.556 |
| Loop diuretic [n (%)] | 8(20.00) | 5(12.50) | 0.363 |
| Dual antiplatelet therapy [n (%)] | 40(100.00) | 40(100.00) | 1.000 |
| Medication at 12 months | |||
| ACEI/ARB/ARNI | 34(85.00) | 33(82.50) | 0.617 |
| Maximum tolerable/standard dose [n (%)] | 28(70.00) | 29(72.50) | 0.805 |
| Beta blocker | 40(100.00) | 40(100.00) | 1.000 |
| Maximum tolerable/standard dose [n (%)] | 29(72.50) | 34(85.00) | 0.172 |
| Aldosterone receptor antagonist [n (%)] | 3(7.50) | 2(5.00) | 1.000 |
| Loop diuretic [n (%)] | 1(2.50) | 4(10.00) | 0.356 |
| Dual antiplatelet therapy [n (%)] | 40(100.00) | 39(97.50) | 1.000 |
| ACEI angiotensin-converting enzyme inhibitor, ARB angiotensin receptor blocker, ARNI angiotensin receptor neprilysin inhibitor | |||
There were no significant differences in liver and kidney function between the two groups at the one-year follow-up (P > 0.05) (Table 8).
| Items | Ivabradine group (40 cases) | Control group (40 cases) | P value |
|---|---|---|---|
| ALT [median (IQR), U/L)] | 18.00(14.00,22.00) | 20.50(14.00,38.00) | 0.380 |
| AST [median (IQR), U/L)] | 20.00(18.00,24.00) | 20.50(16.00,27.50) | 0.890 |
| Creatinine [median (IQR), µmol/L)] | 80.50(67.50,119.50) | 81.00(73.75,101.25) | 0.607 |
| Urea nitrogen [median (IQR), mmol/L)] | 6.20(4.85,8.00) | 7.10(5.13,9.33) | 0.161 |
| Uric acid [median (IQR), mmol/L)] | 377.00(291.75,434.00) | 357.00(315.00,502.00) | 0.477 |
| ALT alanine aminotransferase, AST aspartate aminotransferase | |||
Acute myocardial infarction is mostly caused by acute vascular occlusion due to coronary atherosclerotic plaque rupture and secondary thrombosis, inducing myocardial ischemia, hypoxia and necrosis, which can lead to serious complications, including malignant arrhythmia, heart failure, cardiogenic shock and sudden cardiac death [9]. At present, emergency PCI can quickly open the occluded vessels and restore myocardial blood flow perfusion, but the mortality of myocardial infarction in China has not been decreased to an ideal level [10]. An accelerated heart rate is significantly associated with AMI mortality. The possible mechanisms are as follows [11–13]: increased heart rate can shorten the ventricular diastole and lead to coronary artery hypoperfusion, affecting myocardial blood supply; increased heart rate leads to excessive myocardial oxygen consumption and imbalance of oxygen supply and consumption, which further aggravates myocardial ischemia. At the same time, increased heart rate is often accompanied by excessive activation of sympathetic nerves and elevated catecholamine levels, which can directly induce vascular endothelial injury and myocardial remodeling. Therefore, heart rate should be strictly controlled after PCI to improve the prognosis of patients with myocardial infarction.
Metoprolol is the most commonly used β-blocker in clinical practice and can slow heart rate, reduce myocardial oxygen consumption, decrease catecholamine levels, and inhibit myocardial remodeling. However, long-term and massive use may produce side effects such as negative inotropy, negative conduction, asthma and hypotension [14]. Ivabradine is a highly selective If current inhibitor that can inhibit the sinus node rhythm and thus slow the heart rate. Moreover, the drug can reduce the heart rate without affecting the atrioventricular conduction time and myocardial contractility [15].
In this study, cardiac function was evaluated by echocardiography. LVEF was significantly higher in the ivabradine group than in the control group at 1 week, 3 months and 1 year after PCI, and the difference between the two groups was more significant at 1 year. This suggests that early use of ivabradine can better improve left ventricular systolic function, and the longer the follow-up time, the more significant and sustainable its effect on improving cardiac function will be found. Gerbaud et al. [16] used cardiac magnetic resonance to evaluate myocardial remodeling, and they found that ivabradine added to basic drug therapy could significantly improve left ventricular remodeling in STEMI patients after successful PCI. Xu et al. [17] found that LVEF in the ivabradine group was significantly higher than that in the control group at 3 months after PCI, but there was no significant difference in LVEF between the two groups at 6 months after PCI. It was found that the heart rate of the ivabradine group was significantly lower than that of the control group at 1 week after PCI, suggesting that early use of ivabradine can control the heart rate faster and better. However, the heart rate of the two groups further decreased and tended to be consistent at 3 months and 1 year after PCI, indicating that ivabradine combined with metoprolol had better heart rate control than metoprolol alone in the early stage, but this effect gradually disappeared in the longer follow-up. The early control of heart rate in the ivabradine group may be the fundamental reason for reducing cardiac load and improving myocardial remodeling.
CPET is an important noninvasive method to evaluate cardiopulmonary function and aerobic exercise capacity. Peak oxygen uptake is a strong predictor of exercise capacity in patients with cardiac insufficiency and is closely related to the prognosis of patients [18]. Studies have shown that every 1 ml/(min•kg) increase in peak oxygen uptake can reduce all-cause mortality by approximately 10% [19]. This study found that VO2max, METs, AT heart rate, and peak heart rate were significantly higher in the ivabradine group than in the control group at 1 year after PCI, suggesting that ivabradine can significantly improve the cardiopulmonary function and exercise tolerance of patients. Heart rate recovery (HRR) after an exercise test is affected by the cardiac sympathetic nerve and vagus nerve, which can reflect the regulatory ability of the cardiac autonomic nerve. Delayed or abnormal heart rate recovery is an independent risk factor for predicting cardiovascular disease mortality and can predict the prognosis of patients with ischemic heart disease [20, 21]. The HRR value of the ivabradine group was significantly higher than that of the control group, which may be related to the significant inhibition of sinoatrial node autonomic rhythm by ivabradine. In this study, patients in both groups were followed up for 1 year, and no cardiac death occurred. The proportion of recurrent angina and heart failure in the ivabradine group was lower than that in the control group, which was consistent with the results of the SHIFT study [22]. Meanwhile, the total incidence of MACE at 1 year after PCI in the ivabradine group was significantly lower than that in the control group, which was because ivabradine combined with β-blockers can more significantly reduce the heart rate, increase the coronary flow reserve, and improve vascular endothelial function, thereby reducing the incidence of myocardial ischemia and heart failure and improving the long-term prognosis of patients.
BNP is a reliable indicator for predicting the prognosis of myocardial infarction and is positively correlated with the onset of heart failure in AMI patients [23, 24]. This study found that the BNP of the ivabradine group after PCI was lower than that of the control group, and the difference was statistically significant on Days 2 and 3 after PCI, suggesting that ivabradine can reduce the occurrence of early heart failure after myocardial infarction, probably because it can slow the heart rate earlier and improve cardiac function. This study found that the TnI of the ivabradine group was lower than that of the control group from Day 1 to Day 5 after PCI, and there was a statistically significant difference between the two groups on Day 5 after PCI, suggesting that ivabradine can significantly reduce the degree of myocardial injury in patients, which may be related to its ability to reduce heart rate, myocardial oxygen consumption and myocardial infarction area. Studies have shown that ivabradine can improve myocardial blood supply by increasing coronary artery reserve and thus reduce myocardial infarction area, and this effect is independent of its effect on heart rate reduction [25]. In addition, ivabradine can inhibit oxidative stress, reduce cardiomyocyte inflammation and protect cardiomyocyte viability [26]. It can thicken the ventricular wall of the infarcted area, inhibit infarct expansion, and protect the contractile function and synchrony of the distal viable myocardium [27].
This study is a prospective, single-center randomized controlled study with a small sample size, which may lead to bias in the results. It still needs to be further verified by multicenter and large-sample studies. The lack of placebo and blinding may also have affected the objectivity of the results.
Early use of ivabradine in patients with acute myocardial infarction after PCI can better control heart rate, reduce myocardial injury, improve cardiac function and exercise tolerance of patients, and reduce the incidence of adverse cardiac events, and is worthy of further promotion in clinical practice.
Acknowledgements The authors would like to thank the Science and Technology Commission of Shanghai Municipality for the funding of the research, and thank Professor Kai Hu from University of Würzburg for his guidance and revision of the paper.
Author Contributions
Rui Qing He: Methodology, Writing - Original Draft; Ling Yan Li: Methodology, Writing - Original Draft; Chao Han: Investigation; Wen An: Investigation; Cheng Hao Yang: Data Curation; Zong Jun Liu: Data Curation; Jun Qing Gao: Conceptualization.
Funding This work was supported by The Shanghai Medical Innovation Research Project of “Scientific and Technological Innovation Action Plan” (20Y11910100, 21Y11909600); Scientific Research Hundred Personnel Plan of Shanghai Putuo District Central Hospital (2022-RCJC-01); Shanghai Municipal Health and Health Commission Health Industry Clinical Research Project (20214Y0494); Budget Project of Shanghai University of Traditional Chinese Medicine (2021LK054); Shanghai Putuo District Health System Science and Technology Innovation Project (ptkwws202209).
Data Availability Data will be available upon reasonable request.
Ethics Approval The study was approved by Ethics Committee of Putuo Central Hospital (PTEC-A-2021-22-1).
Consent to Participate All patients signed informed consent to participate in this study.
Consent for Publication The authors affirm that all data collected, analysed, and published will be free from any participants.
Competing Interests The authors declare no competing interests.
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