Table 2.
Baseline for included studies
| N | Study ID | Study groups | Female, N (%) | Age (Mean ± Sd) | Cancer type | Type of chemotherapy | Accumulative dose of chemotherapy | Follow up duration | Definition of LV dysfunction | LVEF | NT-proBNP | Troponin |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | Gulati 2016 [28] | candestran + metoprolol | 30 (100%) | 50.0 ± 8.9 | breast | trastuzumab | NA | NA | NA | 62.2 ± 4.4 | NA | NA |
| candestran + placebo | 32 (100%) | 51.7 ± 10.7 | breast | trastuzumab | NA | 62.3 ± 5.3 | NA | NA | ||||
| metoprolol + placebo | 32 (100%) | 50.5 ± 9.1 | breast | trastuzumab | NA | 63.5 ± 5.0 | NA | NA | ||||
| placebo + placebo | 32 (100%) | 50.8 ± 9.2 | breast | trastuzumab | NA | 63.6 ± 4.1 | NA | NA | ||||
| 2 | Gupta 2017 [29] | enalapril | 31 (70%) | 8.85 ± 3.15 | leukemia, lymphoma | anthracyclines | 272.73 ± 78.62 | 6 months | decrease in LVEF of ≥ 20% from baseline to 6 months | 62.25 ± 5.49 | 49.60 ± 35.97 | 0.01 ± 0.00 |
| placebo | 30 (75%) | 8.77 ± 2.86 | leukemia, lymphoma | anthracyclines | 263.64 ± 80.90 | 56.15 ± 4.79 | 98.60 ± 54.24 | 0.011 ± 0.003 | ||||
| 3 | Kalay 2006 [33] | carvedilol | 22 (88%) | 46.8 ± 14 | breast, lymphoma, and other | anthracyclines | adriamycin = 525.3, epirubicin = 787.9 | 6 months | EF 50% | 70.6 ± 8.0 | NA | NA |
| placebo | 21 (84%) | 49.0 ± 9.8 | breast, lymphoma, other | anthracyclines | adriamycin = 513.6, epirubicin = 770.4 | 69.7 ± 7.3 | NA | NA | ||||
| 4 | Cardinale 2006 [20] | enalapril | 33 (60%) | 47 ± 11 | breast, lymphoma, leukemia, Ewing's sarcoma | anthracyclines | 332 ± 191 | 12 months |
absolute decrease 10 percent units in rest LVEF associated with a decline below the normal limit value (50%).3,4 |
62.4 ± 3.5 | NA | NA |
| control | 39 (67%) | 44 ± 13 | breast, lymphoma, leukemia, Ewing's sarcoma | anthracyclines | 338 ± 167 | 62.8 ± 3.4 | NA | NA | ||||
| 5 | Georgakopoulos 2010 [26] | metoprolol | 20 (48%) | 51.0 ± 18.0 | lymphoma | anthracyclines | 387.5 ± 6.8 | 36 months | NA | 67.7 ± 5.0 | NA | NA |
| enalapril | 21 (49%) | 47.4 ± 16.2 | lymphoma | anthracyclines | 373.1 ± 6.3 | 65.2 ± 7.1 | NA | NA | ||||
| control | 19 (47%) | 49.1 ± 19.4 | lymphoma | anthracyclines | 386.4 ± 5.7 | 67.6 ± 7.1 | NA | NA | ||||
| 6 | Acar 2011 [15] | atorvastatin | 12(60%) | 53.7 ± 14.2 | non-Hodgkin’s lymphoma, multiple myeloma, and leukemia | anthracyclines | NA | 6 months | ejection fraction (EF) of < 50% | 61.3 ± 7.9 | NA | NA |
| control | 11(55%) | 52.6 ± 17.6 | non-Hodgkin’s lymphoma, multiple myeloma, and leukemia | anthracyclines | NA | 62.9 ± 7.0 | NA | NA | ||||
| 7 | Salehi 2011 [41] | placebo | 8 (36%) | 43.50 ± 15.27 | breast, lymphoma | anthracyclines | 540.28 ± 31.17 mg/m2 | 4 months | NA | 58.56 ± 3.62 | NA | NA |
| carvedilol 12.5 mg | 7 (32%) | 45.70 ± 14.16 | breast, lymphoma | anthracyclines | 531.50 ± 29.98 mg/m2 | 60.5 ± 5.07 | NA | NA | ||||
| carvedilol 25 mg | 5 (23%) | 52.52 ± 11.00 | breast, lymphoma | anthracyclines | 521.14 ± 38.97 mg/m2 | 61.00 ± 7.06 | NA | NA | ||||
| 8 | Bosch 2013 [19] | enalapril and carvedilol | 18 (40%) | 49.7 ± 13.9 | leukemia | anthracyclines | 290 ± 189 | 6 months | LVEF declined below its normal limit of 50% | 62 ± 5.9 | 19 ± 7.25 | 0.013 ± 0.008 |
| control | 21(47%) | 50.9 ± 13.2 | leukemia | anthracyclines | 241 ± 162 | 63 ± 5.9 | 21 ± 5.75 | 0.013 ± 0.010 | ||||
| 9 | Kaya 2013 [34] | Nebivolol | 27(100%) | 51.4 ± 9.4 | breast | anthracyclines |
epirubicin = 361 ± 88 adriamycin = 257 ± 29 cyclophosphamid = 2342 ± 870 5-Fluorouracil = 2325 ± 1015 docetaxel = 450 ± 0 |
6 months |
LVEF < 45% at the end of the study |
65.6 ± 4.8 | 65.42 ± 25.37 | NA |
| Placebo | 18(100%) | 50.5 ± 11.1 | breast | anthracyclines |
epirubicin = 348 ± 84 adriamycin = 235 ± 48 cyclophosphamid = 2269 ± 876 5-Fluorouracil = 2291 ± 1042 docetaxel = 337 ± 159 |
66.6 ± 5.5 | 64.09 ± 29.37 | NA | ||||
| 10 | Radulescu 2013 [39] | perindopril | 36 (53%) | 48.24 ± 12.2 | lung, lymphoma, nasopharynx, breast, urinary bladder, and stomach | epirubicin | 550 mg/m2 | 12 months | NA | 58.48 ± 6.12 | NA | NA |
| control | 38 (56%) | 48.24 ± 12.2 | lung, lymphoma, nasopharynx, breast, urinary bladder, and stomach | epirubicin | 550 mg/m2 | 59.46 ± 7.12 | NA | NA | ||||
| 11 | Dessì 2013 [23] | telmisartan | 19 (76%) | 52.9 ± 9 | breast, endometrial, NHL, NSCLC, ovarian, salivary gland | epirubicin | 400 ± 30 mg/m2 | 18 months | LVEF under 55% | 66 ± 5% | NA | NA |
| placebo | 18 (76%) | 53 ± 10 | breast, endometrial, NHL, NSCLC, ovarian, salivary gland | epirubicin | 400 ± 30 mg/m2 | 66 ± 5% | NA | NA | ||||
| 12 | Jhorawat 2014 [32] | Carvedilol | 4 (14.8%) | 43.89 ± 15.66 | lymphoreticular malignancy | anthracycline | 427.96 ± 124.36 | 6 months |
a decline in LVEF of at least five percent to less than 55 percent with accompanying signs or symptoms of HF, or a decline in LVEF of at least 10 percent to below 55 percent without accompanying signs or symptoms |
63.19 ± 7.22 | NA | NA |
| Placebo | 9 (33.3%) | 38.74 ± 18.36 | lymphoreticular malignancy | anthracycline | 395.07 ± 132.82 | 67.56 ± 5.98 | NA | NA | ||||
| 13 | Elitok 2014 [24] | carvedilol | 40 (100%) | 54.3 ± 9.3 | breast cancer | anthracycline | 535.6 mg/m2 | 6 months | NA | 66 ± 6.1 | NA | NA |
| placebo | 40 (100%) | 52.9 ± 11.2 | breast cancer | anthracyline | 523.3 mg/m2 | 65 ± 4.5 | NA | NA | ||||
| 14 | Akpek 2014 [10] | Spironolactone | 0(0%) | 50.0 ± 10.8 | breast cancer | anthracycline | adriamycin = 430.2 ± 52.2, epirubicin = 688.9 ± 136.0 | NA | 67.0 ± 6.1 | 81.33 ± 59.03 | 0.010 ± 0.014 | |
| placebo | 0(0%) | 50.6 ± 10.1 | breast cancer | anthracycline | adriamycin = 394.2 ± 71.9, epirubicin = 688.9 ± 120.5 | 67.7 ± 6.3 | 66 ± 12.03 | 0.011 ± 0.015 | ||||
| 15 | Chotenimitkhun 2015 [21] | statin | 8(57%) | 62 ± 2 | breast cancer, leukemia, and lymphoma | anthracycline | Doxorubicin = 153 ± 35,Daunorubicin = 45 ± 25,Epirubicin = 36 ± 36 | 6 moths | NA | 56.6% ± 1.4% | NA | NA |
| non-statin | 25(67%) | 43 ± 2 | breast cancer, leukemia, and lymphoma | anthracycline | Doxorubicin = 159 ± 20,Daunorubicin = 64 ± 22,Epirubicin = 9 ± 8 | 57.5% ± 1.4% | NA | NA | ||||
| 16 | Boekhout 2016 [18] | Candesartan | 103(100%) | 50 ± 2.33 | breast cancer | trastuzumab | 440 mg/m2 | 21 months | a decline in LVEF of > 15% or a decrease below the absolute value of 45% | 60 ± 1.5 | 27.59 ± 5.26 | 0.014 ± 2.17 |
| placebo | 103(100%) | 51 ± 2.17 | breast cancer | trastuzumab | 440 mg/m2 | 61 ± 1.5 | 31.6 ± 5.86 | 13 ± 1.83 | ||||
| 17 | Ahmad 2016 | Carvedilol | 30 (100%) | 42 ± 6.3 | breast cancer | Doxorubicin | 240 mg/m 2 | NA |
a A 10–50% drop was considered an indication of discontinuation of the chemotherapy |
59.41 ± 4.2 | NA | NA |
| placebo | 40(100%) | 39.9 ± 6.3 | breast cancer | Doxorubicin | 240 mg/m 2 | 61.31 ± 3.21 | NA | NA | ||||
| 18 | Janbabai 2016 [31] | placebo | 31 (88.6%) | 47.06 ± 12.39 | Breast, Wilms tumor, Lung cancer, Bone sarcoma, Hodgkin’s lymphoma | Anthracycline | 366.69 ± 21.76 | 6 months | LVEF < 45% | NA | NA | 0.065 ± 0.0175 |
| enalapril | 33 (97.1%) | 47.76 ± 11.81 | Breast, Wilms tumor, Lung cancer, Bone sarcoma, Hodgkin’s lymphoma | Anthracycline | 363.34 ± 34.87 | 59.61 ± 5.70 | NA | 0.016 ± 0.011 | ||||
| 19 | Nabati 2017 [46] | Placebo | 45(100%) | 47.10 ± 12.17 | breast cancer | Anthracyclines |
doxorubicin = 359.91 ± 27.13 cyclophosphamide = 3390.59 ± 234.67 |
6 months | NA | 61.13 ± 4.97 | NA | 0.146 ± 0.055 |
| carvedilol | 46(100%) | 47.57 ± 8.75 | breast cancer | Anthracyclines |
doxorubicin = 348.56 ± 40.34 0.141 cyclophosphamide = 3653.51 ± 405.64 |
58.72 ± 4.69 | NA | 0.073 ± 0.022 | ||||
| 20 | Pituskin 2017 [38] | placebo | 30(100%) | 51 ± 7 | breast cancer | trastuzumab | 24-month | change in indexed left ventricular end-diastolic volume and LVEF | 61 ± 5 | NA | NA | |
| perindopril | 33(100%) | 50 ± 8 | breast cancer | trastuzumab | 62 ± 5 | NA | NA | |||||
| Bisoprolol | 31(100%) | 53 ± 10 | breast cancer | trastuzumab | 62 ± 4 | NA | na | |||||
| 21 | Avila 2018 [17] | carvedilol | 96(100%) | 50.8 ± 10.10 | breast cancer | Anthracycline | 240 mg/m2 | 6 months | ≥ 10% reduction in LVEF | 64.8 ± 4.7 | 16 ± 2.79 | 0.005 ± 0 |
| placebo | 96(100%) | 52.9 ± 9.05 | breast cancer | Anthracycline | 240 mg/m2 | 65.2 ± 3.6 | 12 ± 2.5 | 0.005 ± 0 | ||||
| 22 | Wihandono 2021 [45] | lisinopril and bisoprolol | 26(100%) | 44,5 ± 7,7 | breast cancer | Anthracyclines | 579.48 ± 65.10 | 5 months | change from baseline LVEF | 65.77 ± 4.56 | NA | NA |
| placebo | 25(100%) | 50,8 ± 7,39 | breast cancer | Anthracyclines | 557.50 ± 47.76 | 65.44 ± 4.55 | NA | NA | ||||
| 23 | Slowik 2020 [42] | ramipril | 48(100%) | 45.67 ± 12.23 | breast cancer | Anthracycline | (doxorubicin dose ≥ 250 mg/m2) | 12 months | decrease in left ventricular LVEF, elevated biomarker levels, and/or HF or cardiac death | 67.33 ± 3.82 | NA | NA |
| placebo | 48(100%) | 45.67 ± 8.41 | breast cancer | anthracycline | 66 ± 3.82 | NA | NA | |||||
| 24 | Sherafati 2019 | Carvedilol | 27(100%) | 46.5 | breast cancer | trastuzumab | NA | 3 months | (LVEF < 50% or a decrease in EF over 10%) | 56.3 ± 3.7 | NA | NA |
| control | 38(100%) | breast cancer | trastuzumab | NA | 56.9 ± 3.6 | NA | NA | |||||
| 25 | Nabati 2019 [37] | placebo | 39(100%) | 50.74 ± 12.440 | breast cancer | anthracycline | 337.83 ± 42.60 | 6 months | changes in the LVEF and the global longitudinal strain (GLS) | 55.10 ± 5.09 | NA | NA |
| Rosuvastatin | 38(100%) | 47.74 ± 9.70 | breast cancer | anthracycline | 339.44 ± 39.00 | 55.05 ± 4.84 | NA | NA | ||||
| 26 | Martha 2020 [44] | carvedilol | 40(100%) | 48 ± 10 | breast cancer |
5-fluorouracil, Adriamycin, Cyclophosphamide (FAC) |
consisted of 5-fluorouracil 600 mg/m2, Adriamycin 60 mg/m2, and cyclophosphamide 600 mg/m2 |
< 1 month | reduction of LVEF > 10%, to a value of < 53% | NA | NA | NA |
| control | 40(100%) | 48 ± 8 | breast cancer |
5-fluorouracil, Adriamycin, Cyclophosphamide (FAC) |
NA | NA | NA | |||||
| 27 | Heck 2021 (from gulti 2016) [30] | Candesartan–metoprolol | 28(100%) | 50 ± 9 | breast cancer | anthracyclines | NA | 24 months |
defined as LVEF < 53% in combination with either an absolute decrease of > 10% in LVEF as determined by CMR or clinical heart |
NA | NA | NA |
| Candesartan–placebo | 32(100%) | 52 ± 11 | breast cancer | NA | NA | NA | NA | |||||
| Placebo–metoprolol | 30(100%) | 51 ± 9 | breast cancer | NA | NA | NA | NA | |||||
| Placebo–placebo | 30(100%) | 51 ± 9 | breast cancer | NA | NA | NA | NA | |||||
| 28 | Guglin 2019 [27] | carvedilol | 156(100%) | 51.58 ± 10.93 | breast cancer | anthracyclines | NA | 24 months | decrease in LVEF of > 10% in patients whose LVEF is > 50%; or a drop in LVEF of at least 5% from baseline in patients whose LVEF decreases to < 50% | 62.55 ± 6.61 | 38.3 ± 40.2 | NA |
| Lisinopril | 158(100%) | 50.58 ± 10.91 | breast cancer | anthracyclines | NA | 62.97 ± 6.18 | 31.3 ± 16.7 | NA | ||||
| Placebo | 154(100%) | 51.11 ± 10.32 | breast cancer | anthracyclines | NA | 62.24 ± 6.09 | 37.5 ± 39.4 | NA | ||||
| 29 | Esfandbod 2021 [35] | Carvedilol | 30(100%) | 47.6 ± 9.64 | breast cancer | Trastuzumab | NA | 12 months |
1- Global LVEF decrease 2- Interventricular LVEF decrease 3- 5% or more decrease from basal LVEF or EF < 55% in symptomatic patients 4- 10% or more decrease from basal LVEF or EF < 50% in asymptomatic patients |
55 ± 1.03 | NA | NA |
| Placebo | 30(100%) | 46.2 ± 8.59 | breast cancer | Trastuzumab | NA | 54.9 ± 0.45 | NA | NA | ||||
| 30 | GEORGAKOPOULOS 2019(10 years follow up) [25] | Metoprolol | 20 (47%) | 51.0 ± 18.0 | Lymphoma | Anthracyclines | NA | 120 months |
difference of 10% between the LVEF values at each visit and the baseline value, and LVEF < 50% |
65.7 ± 5.0 | NA | NA |
| Enalapril | 21 (49%) | 47.4 ± 16.2 | Lymphoma | Anthracyclines | NA | 65.2 ± 7.1 | NA | NA | ||||
| control | 19(47%) | 49.1 ± 19.4 | Lymphoma | Anthracyclines, | NA | 67.6 ± 7.1 | NA | NA | ||||
| 31 | Farahani 2019 [36] | Carvedilol | 36(100%) | 57.3 ± 7.3 | breast cancer | Trastuzumab | 3 months | LVEF reductions of greater than 10% to less than 50% or LVEFs of less than 45% | 54.93 ± 4.26 | NA | NA | |
| placebo | 36(100%) | 57.4 ± 8.8 | breast cancer | Trastuzumab | 54.32 ± 5.32 | NA | NA | |||||
| 32 | Davis 2019 [22] | Eplerenone | 22(100%) | 53.9 ± 2.0 | breast cancer | Anthracycline | 240 mg/m2 | 6-month | a decline in LVEF of 10% to an absolute value of < 50%; | 63.2 ± 3.9 | 28.5 ± 14, 36 | NA |
| placebo | 22(100%) | 49.1 ± 12.8 | breast cancer | Anthracycline | 64.4 ± 4.2 | 31.0 ± 9, 53 | NA | |||||
| 33 | Rizka 2021 [40] | ACE Is | 15(100%) | 55 ± 7.387 | breast cancer | anthracycline | NA | NA | NA | NA | NA | 0.0120 ± 0.0077 |
| control | 15(100%) | 48.93 ± 9.573 | breast cancer | anthracycline | NA | NA | NA | 0.0127 ± 0.0059 |
Abbreviations: ACEI Angiotensin-converting enzyme inhibitor, LVEF Left ventricular Ejection Fraction, NA Not Applicable, BNP B-type natriuretic peptide