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Table 1 Summary of studies for primary prevention of anthracycline-induced cardiotoxicity with beta-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and aldosterone antagonists

From: Strategies to prevent anthracycline-induced cardiotoxicity in cancer survivors

Reference Medications Patients (groups), Na Follow-Up, mean (SD) Months Imaging Modality Results by group
Avila et al. [86] Carvedilol (3.125 mg BID increasing every 3 weeks to max 25 mg BID) vs. placebo 192 (96/96) 6 Echo Carvedilol LVEF 65.2% → 63.9%
Placebo LVEF 64.8% → 63.9%
P = 0.84
-Lower troponin I levels in the carvedilol group (P = 0.003)
-Lower incidence of diastolic dysfunction in the carvedilol group (P = 0.04)
Kalay et al. [87] Carvedilol (12.5 mg) daily vs. placebo 50 (25/25) 5.2 (1.2) Echo Carvedilol: LVEF 70.5% → 69.7%
Placebo: LVEF 68.9% → 52.3%†
RR: 0.2 (0.03–1.59)
Tashakori et al. [88] Carvedilolb vs. control 70 (30/40) 1 week Strain by Speckle Tracking Echo No significant reduction in strain and strain-rate parameters after intervention, compared to control group (P < 0.001)
Elitok et al. [89] Carvedilolc vs. control 80 (40/40) 6 Echo - Mean LVEF, LVFS, and LV dimensions similar before and after cancer therapy
- Significantly worse LV basal septal (0.7 vs. 0.94) and lateral peak systolic strain (0.72 vs. 1.08) in control group after treatment while these measures did not differ between treatment groups at baseline.
- No clinical cardiotoxic events in either group
Nabati et al. [96] Carvedilol 91 (45/46) 6 Echo - Carvedilol: No change in mean LVEF
- Control: Mean drop of 10% LVEF
Placebo group had a higher frequency of TnI concentrations > 0.05 at 30 days (48.6% vs. 24.4%, P = 0.03)
Jhorawat et al. [90] Carvedilolc vs. control 54 (27/27) 6 Echo Carvedilol: LVEF 63.19% ➔ 63.88%
LVFS 34% ➔ 34.6%
Control: LVEF 67.27% ➔ 60.82%†
LVFS 38.48% ➔ 34.6†
LV end-systolic diameter
Control mean (SD): 28.26 (5.50 mm➔ 31.25 (6.50) mm†)
Carvedilol: unchanged
Kaya et al. [91] Nebivolol (5 mg) daily vs. placebo f 45 (27/18) 6 Echo Nebivolol: LVEF 65.6% → 63.8%
Placebo: LVEF 66.6% → 57.5%†
(P = 0.01)
Cardinale et al. [93] Enalapril at start of chemotherapy (prevention arm) vs. troponin triggered enalapril therapy 273 (136/137) 12 Echo Troponin elevation incidence: Prevention group: 23% vs. Troponin triggered group 26% (P = 0.50)
Cardiotoxicity incidence: 2 in prevention group vs. 1 in troponin-triggered group
Janbabai et al. [94] Enalapril (17.94 [4.10] mg) vs. control 69 (34/35) 6 Echo Δ mean LVEF from baseline at 6 months: 0.55 vs. -13.3, P < 0.001
In the enalapril group, tissue Doppler, E/e’ ratio, mean LVEF and cTnI and CK-MB levels were significantly unchanged compared to the controls.
Nakamae et al. [95] Valsartan (80 mg) 40 (20/20) 7 days Echo Valsartan significantly inhibited the dilatation of LVDd (P = 0.01), elevation of BNP (P = 0.001), and prolongation of the QTc interval and QTc dispersion (P < 0.001 and P = 0.02, respectively)
Georgakopoulos et al. [97] Metoprolol d vs. enalapril d vs. placeboe 125 (42/43/40) 31 (Longest 36) Clinical Cardiotoxicity incidence:
Metoprolol: 1 vs. 3, not significant
Enalapril: 2 vs. 3, not significant
No difference in echocardiographic variables among 3 groups at 12 months
Comments:
-Results published as a letter not full article
-Appears to be a cohort study, not a randomized trial
-Cardiotoxicity not defined
Bosch et al. [11] Enalapril (8.6 [5.9] mg) + Carvedilol (23.8 [17] mg)
vs. no treatment f
90 (45/45) 6 Echo and CMR Enalapril + carvedilol: LVEF 63.3% → 62.9%
Control: LVEF 64.6% → 57.9%† cTnI concentrations did not differ between 2 groups (P = 0.59)
Gulati et al. [12] Candesartan (32 mg) g + metoprolol (100 mg) vs.
Candesartan + placebo vs.
Metoprolol g + placebo vs.
Placebo + placebo
126 (30/32/32/ 32) 10–61 weeks CMR Δ LVEF from baseline
1. Candesartan: − 0.8 vs. -2.6%, P = 0.023
2. Metoprolol: − 1.6 vs. -1.8%, P = 0.77
Data were analyzed differently (comparing all those who received a drug to those who did not) from factorial design of the trial.
Akpek et al. [104] Spironolactone h vs. placebo 83 (43/40) 24.0 [2.9] weeks Echo Spironolactone LVEF 67% → 65.7% (P = 0.094)
Placebo LVEF 67.7% → 53.6% (P < 0.001)
Troponin and NT-proBNP remained in normal limits.
Increase in the control group was more than in the spironolactone group
Gupta et al. (PEDIATRIC) [105] Enalaprili vs. placebo 84 (44/40) 6 Echo Enalapril LVEF 65.73% → 62.25%
Placebo LVEF 64.85% → 56.15%†
> 20% decrease in LVEF:
Enalapril - 0
Placebo- 3 patients (8%)
Higher proBNP in placebo group (P < 0.001)
Higher cTnI level in placebo group (P = 0.035)
El-Shitany et al. (PEDIATRIC) [106] Carvedilol j vs. control 50 (25/25) After last doxorubicin dose Echo -FS (2D) and GPSS (2DS) significantly increased in carvedilol treated group.
-Carvedilol pretreatment inhibited ADR-induced increase in plasma troponin I and LDH. (Post treatment troponin, 0.061 vs. 0.023, P ≤ 0.05. Post treatment, LDH 957 vs. 410, P ≤ 0.05)
  1. LVEF, left ventricular ejection fraction; cTnI, cardiac troponin I; FS (2D), fractional shortening measured by 2-dimensional echocardiography; CK-MB, creatine kinase-MB; E/e’ ratio, early mitral inflow velocity: mitral annular early diastolic velocity ratio; GPSS (2DS), global peak-systolic strain measured by 2-dimensional echocardiography; ADR, doxorubicin; LDH, lactate dehydrogenase
  2. † Statistically significant between baseline and 6 months (P < 0.05)
  3. a Numbers in parentheses are the numbers of patients in intervention and control or placebo groups, respectively
  4. b Carvedilol 6.25 mg daily during chemotherapy
  5. c12.5 mg oral carvedilol daily for 6 months during chemotherapy
  6. dMedications titrated as tolerated
  7. eMedications started on the first day of chemotherapy and continued throughout the study
  8. fMedications started within 1 week before the first chemotherapy cycle and continued for 6 months
  9. gStarting dose was 8 mg for candesartan cilexetil and 50 mg for metoprolol succinate; target dose 32 and 100 mg, respectively
  10. h Dose was 25 mg/day started 1 week before the start of chemotherapy until 3 weeks after end of chemotherapy
  11. iDose was 0.1 mg/kg/day once a day from the first day of chemotherapy for 6 months
  12. jStarting carvedilol dose was 0.1 mg kg− 1 d− 1 in two divided doses, increased weekly until reaching a dose of 1 mg/kg before the last dose of doxorubicin