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

Avila et al. [86]

Carvedilol (3.125 mg BID increasing every 3 weeks to max 25 mg BID) vs. placebo

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

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]

Carvedilol^b vs. control

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]

Carvedilol^c vs. control

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

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]

Carvedilol^c vs. control

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

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

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

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)

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. placebo^e

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

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

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

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

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

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)