Ivabradine for the Prevention of Anthracycline-Induced Cardiotoxicity in Female Patients with Primarily Breast Cancer: A Prospective, Randomized, Open-Label Clinical Trial
Abstract
:1. Introduction
2. Materials and Methods
2.1. Study Design
2.2. Study Participants
2.3. Randomization, Allocation, and Intervention
2.4. Study Procedures
2.5. Study Endpoints
- Incidence of myocardial damage as measured by elevated high-sensitivity cardiac Tn I.
- Incidence of myocardial injury according to elevated NT-proBNP levels.
- Incidence of LV diastolic dysfunction.
- Incidence of LV systolic dysfunction measured by EF and symptomatic HF.
- Incidence of RV dysfunction.
- Changes in myocardial work parameters by the 2D strain–pressure loop.
- Incidence of adverse effects of ivabradine.
2.6. Statistical Analysis
3. Results
3.1. Cardiovascular Toxicity Risk Stratification before Anticancer Therapy
3.2. Ivabradine Dosage and Efficacy
3.3. Primary Endpoint
3.4. Secondary Endpoints
3.4.1. Changes in the Levels of Tn I
3.4.2. Changes in NT-proBNP Levels
3.4.3. LV Diastolic Dysfunction
3.4.4. LV Systolic Dysfunction and Symptomatic HF
3.4.5. RV Dysfunction
3.4.6. Myocardial Work Indices
3.4.7. Mild Asymptomatic Cancer-Therapy-Related Cardiac Dysfunction
3.4.8. Incidence of Adverse Effects of Ivabradine
4. Discussion
4.1. Reduction in the GLS during Cardiotoxic Chemotherapy
4.2. Increase in Tn I Levels
4.3. Increase in Natriuretic Peptide Levels
4.4. Development of Diastolic Dysfunction
4.5. Deterioration of LV Systolic Function
4.6. Alterations in Myocardial Performance
5. Study Limitations
6. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Baseline Characteristics | Ivabradine n = 21 (%) | Controls n = 27 (%) | p-Value |
---|---|---|---|
Age, years (mean ± SD, range) | 47.8 ± 9.9, 34–66.5 | 48 ± 10.2, 34–66.5 | 0.935 |
Cancer type, n (%) | 0.449 | ||
Right breast | 10 (47.6) | 10 (37) | |
Left breast | 11 (52.4) | 14 (51.9) | |
Both breasts | 0 | 1 (3.7) | |
Sarcoma | 0 | 2 (7.4) | |
Cancer stage, n (%) | 0.509 | ||
I | 2 (9.5) | 6 (22.2) | |
II | 14 (66.7) | 15 (55.6) | |
III | 5 (23.8) | 5 (18.5) | |
IV | 0 | 1 (3.7) | |
Cancer grade, n (%) | 0.309 | ||
1 | 0 | 0 | |
2 | 13 (65) | 13 (50) | |
3 | 7 (35) | 13 (50) | |
HER2, n (%) | 0.333 | ||
Positive | 7 (35) | 6 (22.2) | |
Negative | 13 (65) | 21 (77.8) | |
BRCA, n (%) | 0.928 | ||
Positive | 3 (15.8) | 4 (14.8) | |
Negative | 16 (84.2) | 23 (85.2) | |
Chemotherapy, n (%) | 0.060 | ||
Adjuvant | 10 (47.6) | 20 (74.1) | |
Neoadjuvant | 11 (52.4) | 7 (25.9) | |
Anthracyclines, n (%) | 0.545 | ||
Doxorubicin | 15 (71.4) | 21 (77.8) | |
Epirubicin | 6 (28.6) | 6 (22.2) | |
Cumulative anthracycline dose | 0.425 | ||
Doxorubicin, mg/m2 (mean ± SD) | 236 ± 70 | 246 ± 69 | |
Epirubicin, mg/m2 (mean ± SD) | 360 ± 70 | 360 ± 70 | |
CV risk factors, n (%) | |||
Hypertension | 3 (15) | 2 (7.4) | 0.404 |
Diabetes | 0 | 0 | |
Dyslipidaemia | 13 (65) | 21 (77.8) | 0.333 |
Smoking | 1 (5) | 6 (22.2) | 0.101 |
Obesity (BMI > 30 kg/m2) | 4 (19) | 2 (7.4) | 0.226 |
Kidney dysfunction (GFR < 60 mL/min./1.73 m2) | 0 | 0 | |
Cardiotoxicity risk group, n (%) | 0.519 | ||
Low | 17 (81) | 23 (85.2) | |
Medium | 4 (19) | 3 (11.1) | |
High | 0 | 1 (3.7) | |
Very high | 0 | 0 | |
HF stage, n (%) | 0.356 | ||
A | 4 (19) | 4 (14.8) | |
B | 4 (19) | 8 (29.6) | |
C | 0 | 1 (3.7) | |
D | 0 | 0 | |
Anaemia (Hb < 117 g/L), n (%) | 12 (60) | 15 (55.6) | 0.761 |
CRP > 5 mg/L, n (%) | 2 (9.5) | 5 (18.5) | 0.381 |
Vitamin D < 75 nmol/L, n (%) | 12 (70.6) | 19 (86.4) | 0.226 |
Myocardial damage markers at baseline, n (%) | |||
Tn I > 16 ng/L | 0 | 0 | |
NT-proBNP > 125 ng/L | 3 (14.3) | 9 (33.3) | 0.131 |
GLS > −18% | 0 | 1 (3.7) | 0.373 |
LVEF < 55% | 0 | 0 | |
Diastolic LV dysfunction | 1 (4.8) | 2 (7.4) | 0.707 |
Echocardiographic parameters at baseline, n (%) | |||
LAVI > 34 mL/m2 | 5 (23.8) | 5 (18.5) | 0.654 |
Transmitral E velocity > 50 cm/s | 7 (33.3) | 10 (37) | 0.790 |
Transmitral A velocity < 60 to < 120 cm/s | 12 (57.1) | 11 (40.7) | 0.259 |
Transmitral E/A ratio < 0.8 to > 2.0 | 7 (33.3) | 6 (22.2) | 0.390 |
Mitral E/e’ ratio > 14 | 0 | 0 | |
e’ med. < 7 cm/s | 1 (4.8) | 4 (14.8) | 0.258 |
e’ lat. < 10 cm/s | 2 (9.5) | 2 (7.4) | 0.792 |
IVRT < 70 to > 100 msec | 12 (57.1) | 8 (29.6) | 0.037 |
Transmitral E velocity DT < 160 to > 220 msec | 11 (52.4) | 9 (33.3) | 0.184 |
RV S’ < 9.5 cm/s | 0 | 0 | |
TAPSE < 17 cm | 0 | 0 | |
2D LVEF < 55% | 0 | 0 | |
GWI < 1310 mmHg% | 0 | 0 | |
GCW < 1543 mmHg% | 0 | 0 | |
GWW > 287 mmHg% | 0 | 0 | |
GWE < 90% | 1 (5.3) | 0 | 0.376 |
3D LVEF< 55% * | 0 | 0 |
Parameter | All (n = 48) | Ivabradine (n = 21) | Controls (n = 27) | p-Value |
---|---|---|---|---|
Baseline | ||||
2D LVEF (mean ± SD) | 64 ± 4.0 | 63.5 ± 3.4 | 64.4 ± 4.5 | 0.478 |
3D LVEF (mean ± SD) | 64.3 ± 4.1 | 62.7 ± 4.0 | 65.5 ± 3.8 | 0.055 |
RV function | ||||
TAPSE (mean ± SD) | 22 ± 2.7 | 22.2 ± 3.4 | 21.8 ± 2.2 | 0.661 |
RV S’ (mean ± SD) | 14.8 ± 1.6 | 14.4 ± 1.3 | 15.07 ± 1.8 | 0.152 |
Myocardial work indices | ||||
GWI (median; Q1–Q3; range) | 2055.5 (1895–2288; 1552–2904) | 2090 (1911–2341; 1552–2697) | 2021 (1846–2288; 1571–2904) | 0.820 |
GCW (mean ± SD) | 2471.3 ± 359.2 | 2445.2 ± 404.4 | 2492.8 ± 325 | 0.674 |
GWW (median; Q1–Q3; range) | 98 (75–131; 35–263) | 82 (63–144; 35–263) | 105 (77–131; 38–156) | 0.622 |
GWE (median; Q1–Q3; range) | 95 (95–97; 86–98) | 96 (94–97; 86–98) | 95 (95–97; 93–98) | 0.826 |
After 2 anthracyclines cycles | ||||
2D LVEF (mean ± SD) | 63.3 ± 4.0 | 62.1 ± 3.4 | 64.0 ± 4.3 | 0.129 |
3D LVEF (mean ± SD) | 63.6 ± 2.6 | 63.5 ± 2.3 | 63.8 ± 3.0 | 0.751 |
RV function | ||||
TAPSE (mean ± SD) | 21.5 ± 2.9 | 22 ± 3.1 | 21.1 ± 2.7 | 0.327 |
RV S’ (mean ± SD) | 14.1 ± 1.7 | 14.3 ± 1.4 | 14.0 ± 1.8 * | 0.534 |
Myocardial work indices | ||||
GWI (median; Q1–Q3; range) | 1911.5 (1671–2229.5; 1043–2587) | 1959 (1766–2253; 1043–2587) | 1826 (1632–2206; 1416–2470) * | 0.412 |
GCW (mean ± SD) | 2235.3 (308.1) | 2278.5 (300.8) | 2203.4 (316.2) * | 0.453 |
GWW (median; Q1–Q3; range) | 84 (68.5–108; 27–438) | 81 (48–125; 35–438) | 86 (70–106; 27–226) | 1.000 |
GWE (median; Q1–Q3; range) | 96 (95–96.5; 84–98) | 96 (95–97; 84–98) | 95 (95–96; 90–98) | 0.348 |
After 4 anthracyclines cycles | ||||
2D LVEF (mean ± SD) | 61.4 ± 5.492 | 62 ± 3.1 * | 61.1 ± 6.7 * | 0.534 |
3D LVEF (mean ± SD) | 63.0 ± 3.8 | 63.1 ± 4.3 | 63 ± 3.3 * | 0.964 |
RV function | ||||
TAPSE (mean ± SD) | 21.3 ± 2.9 | 22.2 ± 2.5 | 20.7 ± 3.0 | 0.087 |
RV S’ (mean ± SD) | 14.4 ± 1.3 | 14.4 ± 1.7 | 14.4 ± 1.1 | 0.902 |
Myocardial work indices | ||||
GWI (median; Q1–Q3; range) | 1906.5 (1747.5–2111.5; 684–2518) | 1946 (1616–2240; 1468–2518) * | 1890 (1769–2073; 684–2453) * | 0.591 |
GCW (mean ± SD) | 2205.5 ± 356.1 | 2257.9 ± 388.7 * | 2169.3 ± 334.7 * | 0.423 |
GWW (median; Q1–Q3; range) | 89 (59–114; 23–150) | 76.5 (61–107; 32–149) | 96 (58–121; 23–150) | 0.424 |
GWE (median; Q1–Q3; range) | 96 (95–97; 84–98) | 96 (95–97; 94–98) | 95 (94–97; 84–98) | 0.113 |
At 6 moths follow-up | ||||
2D LVEF (mean ± SD) | 61.8 ± 4.4 | 61.2 ± 3.5 * | 62.1 ± 4.9 * | 0.493 |
3D LVEF (mean ± SD) | 62.3 ± 4.7 | 61.7 ± 5.1 | 62.8 ± 4.4 * | 0.512 |
RV function | ||||
TAPSE (mean ± SD) | 21.3 ± 2.7 | 21.3 (2.3) | 21.3 ± 3 | 0.972 |
RV S’ (mean ± SD) | 14.5 ± 2.04 | 14.2 (1.7) | 14.6 ± 2.3 | 0.497 |
Myocardial work indices | ||||
GWI (median; Q1–Q3; range) | 1839.5 (1637–2084.5; 1055–2677) | 1979.5 (1665–2339; 1396–2677) * | 1795 (1632–2009; 1055–2171) * | 0.044 |
GCW (mean ± SD) | 2134.1 ± 357.0 | 2290.6 ± 373.1 | 2025.8 ± 307.8 * | 0.014 |
GWW (median; Q1–Q3; range) | 100.5 (70–142; 29–266) | 104.5 (75–150; 42–260) | 96.5 (65–132; 29–266) | 0.676 |
GWE (median; Q1–Q3; range) | 95 (92.5–96; 87–98) | 95 (94–96; 90–98) | 95 (92–96; 87–98) | 0.709 |
Parameters | All (n = 48) | Ivabradine (n = 21) | Controls (n = 27) | p-Value |
---|---|---|---|---|
Baseline | ||||
Tn I (median; Q1–Q3; range) | 1; 0–1.5; 0–5 | 1; 0–1; 0–3 | 1; 0–2; 0–5 | 0.465 |
NT-proBNP (median; Q1–Q3; range) | 70.8 (59.2–128.3; 21–846.6) | 68.5 (60.3–98; 21–190.5) | 74.8 (58.3–152; 47–846.6) | 0.418 |
After 2 anthracyclines cycles | ||||
Tn I (median; Q1–Q3; range) | 3 (2–5; 0–172) | 3 (2–4; 1–9) * | 3 (2–6; 0–172) * | 0.579 |
NT-proBNP (median; Q1–Q3; range) | 82.1 (55.3–130.6; 26.6–945) | 84 (52.4–138; 32–281.6) | 80.2 (65.7–116.4; 26.6–945) | 0.918 |
After 4 anthracyclines cycles | ||||
Tn I (median; Q1–Q3; range) | 12 (7–24; 2–73) | 10 (6–21; 2–73) * | 14 (9–31; 2–70) * | 0.444 |
NT-proBNP (median; Q1–Q3; range) | 84 (49.3–148; 26.9–16,048.7) | 80 (53.4–153.1; 26.9–233.4) | 84 (44–148; 29.5–16,048.7) | 0.908 |
At 6 months follow-up | ||||
Tn I (median; Q1–Q3; range) | 5.5 (3–13; 1–109) | 4 (3–7; 1–42) * | 7.5 (3–20; 2–109) * | 0.124 |
NT-proBNP (median; Q1–Q3; range) | 84.4 (51.2–150.4; 20–10,032.7) | 71.8 (49.7–131.1; 29.8–504.9) | 86.4 (57.2–163.8; 20–10,032.7) | 0.334 |
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Čiburienė, E.; Aidietienė, S.; Ščerbickaitė, G.; Sadauskienė, E.; Sudavičienė, D.; Baltruškevičienė, E.; Brasiūnienė, B.; Drobnienė, M.; Čelutkienė, J. Ivabradine for the Prevention of Anthracycline-Induced Cardiotoxicity in Female Patients with Primarily Breast Cancer: A Prospective, Randomized, Open-Label Clinical Trial. Medicina 2023, 59, 2140. https://doi.org/10.3390/medicina59122140
Čiburienė E, Aidietienė S, Ščerbickaitė G, Sadauskienė E, Sudavičienė D, Baltruškevičienė E, Brasiūnienė B, Drobnienė M, Čelutkienė J. Ivabradine for the Prevention of Anthracycline-Induced Cardiotoxicity in Female Patients with Primarily Breast Cancer: A Prospective, Randomized, Open-Label Clinical Trial. Medicina. 2023; 59(12):2140. https://doi.org/10.3390/medicina59122140
Chicago/Turabian StyleČiburienė, Eglė, Sigita Aidietienė, Greta Ščerbickaitė, Eglė Sadauskienė, Diana Sudavičienė, Edita Baltruškevičienė, Birutė Brasiūnienė, Monika Drobnienė, and Jelena Čelutkienė. 2023. "Ivabradine for the Prevention of Anthracycline-Induced Cardiotoxicity in Female Patients with Primarily Breast Cancer: A Prospective, Randomized, Open-Label Clinical Trial" Medicina 59, no. 12: 2140. https://doi.org/10.3390/medicina59122140