Potential role of angiotensin-converting enzyme inhibitors vs beta-blockers in preventing anticancer agents-induced cardiotoxicity: A systematic review and meta-analysis

Table 1 Tabulated representation of baseline characteristics of included randomized controlled trials

Ref.	Type of study	Type of malignancy	Anti-cancer agent used	Beta blocker used	ACEI used	Location	Total study population (n)	Beta blocker (n)	ACEI/ARBs (n)	Duration of study
Pituskin et al[17], 2017	Randomized control trial	Breast	Transtuzumab	Bisoprolol	Perindopril	Canada	64	31	33	3 years
Guglin et al[18], 2019	Randomized control trial	Breast cancer	Transtuzumab	Carvedilol	Lisinopril	United States	314	156	158	12 months
Barletta et al[19], 2023	Phase 3 Randomized control trial	Breast cancer	Anthracycline	Bisoprolol	Ramipril	Italy	132	66	66	2 years
Georgakopoulos et al[20], 2010	Randomized control trial	Lymphoma	Anthracycline	Metoprolol	Enalapril	Greece	85	42	43	36 months

ACEI: Angiotensin-converting enzymes inhibitors; ARB: Angiotensin II receptor blockers.

Table 2 Tabulated representation of baseline characteristic of included, n (%)/mean ± SD

Characteristics		Pituskin et al[17], 2017		Guglin et al[18], 2019		Barletta et al[19], 2023		Georgakopoulos et al[20], 2010
Subgroups		BB	ACEI/ARB	BB	ACEI/ARB	BB	ACEI/ARB	BB	ACEI/ARB
Age (years)		53 ± 10	50 ± 8	51.58 ± 10.93	20.58 ± 10.91	47 (31-71)	48.5 (23-68)	51.0 ± 18.0	47.4 ± 16.2
Female		31 (100)	33 (100)	156 (100)	156 (100)	66 (100)	66 (100)	20 (48)	21 (49)
Comorbidities	DM	3 (10)	1 (3)	4 (2.56)	5 (3.23)	-	-	10 (24)	3 (7)
	HTN	3 (5)	0	2 (6)	6 (3.79)	-	-	10 (24)	14 (33)
	Smoking	3 (10)	2 (6)	-	-	12 (18.2)	6 (9.1)	9 (21)	8 (19)
BMI (IQR)		30.5 ± 6.2	29.4 ± 6.5	28.26 ± 6.17	28.01 ± 6.86	-	-	25.7 ± 4.7	25.6 ± 5.1
Baseline parameters	SBP (mmHg)	121 ± 12	126 ± 13	124.57 ± 17.7	125.76 ± 17.63	128.8	123.0	-	-
	DBP (mmHg)	74 ± 6	78 ± 11	73.82 ± 10.38	75.73 ± 10.39	74.8	75.0	-	-
	Heart rate (bpm)	72 ± 9	82 ± 14	76.8 ± 20.8	60.2 ± 27.2	74	74	-	-
	LVEF (%)	62 ± 4	62 ± 5	62.55 ± 6.61	62.97 ± 6.18	-	-	67.7 ± 5.0	65.2 ± 7.1

BB: Beta-blockers; ACEI: Angiotensin-converting enzyme inhibitors; DM: Diabetes mellitus; HTN: Hypertension; BMI: Body mass index; IQR: Interquartile range; SBP: Systolic blood pressure; DBP: Diastolic blood pressure; LVEF: Left ventricular ejection fraction.

Table 3 Certainty of evidence assessment using grading of recommendations assessments, development, and evaluation

Certainty assessment							No. of patients		Effect		Certainty	Importance
No. of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	Change in LVEF	Placebo	Relative (95%CI)	Absolute (95%CI)
Change in LVEF
4	Randomised trials	Not serious	Not serious	Not serious	Not serious	None	345	335	-	SMD 0.46 higher (0.14 lower to 1.06 higher)	⊕⊕⊕⊕ high	CRITICAL
Cardiotoxicity
3	Randomised trials	Not serious	Not serious	Not serious	Not serious	None	68/279 (24.4%)	63/272 (23.2%)	RR 1.07 (0.66 to 1.75)	16 more per 1000 (from 79 fewer to 174 more)	⊕⊕⊕⊕ high	CRITICAL
Early cardiotoxicity
2	Randomised trials	Not serious	Not serious	Not serious	Not serious	None	14/123 (11.4%)	16/114 (14.0%)	RR 0.79 (0.23 to 2.69)	29 fewer per 1000 (from 108 fewer to 237 more)	⊕⊕⊕⊕ high	CRITICAL
Late cardiotoxicity
2	Randomised trials	Not serious	Not serious	Not serious	Not serious	None	9/123 (7.3%)	4/114 (3.5%)	RR 2.09 (0.66 to 6.68)	38 more per 1000 (from 12 fewer to 199 more)	⊕⊕⊕⊕ high	CRITICAL
Change in LVEDD
2	Randomised trials	Not serious	Not serious	Not serious	Serious1	None	123	112	-	SMD 0.41 lower (0.98 lower to 0.16 higher)	⊕⊕⊕◯ moderate1	CRITICAL
Change in E/E’
2	Randomised trials	Not serious	Not serious	Not serious	Serious1	None	156	146	-	SMD 0.31 lower (0.54 lower to 0.08 lower)	⊕⊕⊕◯ moderate1	CRITICAL
Change in E/A
2	Randomised trials	Not serious	Not serious	Not serious	Serious1	None	156	192	-	SMD 0.04 lower (0.26 lower to 0.17 higher)	⊕⊕⊕◯ moderate1	CRITICAL
Total AEs
2	Randomised trials	Not serious	Not serious	Not serious	Not serious	None	20/170 (11.8%)	15/153 (9.8%)	RR 1.23 (0.64 to 2.35)	23 more per 1000 (from 35 fewer to 132 more)	⊕⊕⊕⊕ high	CRITICAL
Dizziness
2	Randomised trials	Not serious	Not serious	Not serious	Serious1	None	33/250 (13.2%)	16/237 (6.8%)	RR 2.04 (1.18 to 3.53)	70 more per 1000 (from 12 more to 171 more)	⊕⊕⊕◯ moderate1	CRITICAL
Hypotension
2	Randomised trials	Not serious	Not serious	Not serious	Serious1	None	22/199 (11.1%)	6/200 (3.0%)	RR 3.50 (1.50 to 8.16)	75 more per 1000 (from 15 more to 215 more)	⊕⊕⊕◯ moderate1	CRITICAL
Palpatation
2	Randomised trials	Not serious	Not serious	Not serious	Serious1	None	11/137 (8.0%)	6/121 (5.0%)	RR 1.54 (0.60 to 3.98)	27 more per 1000 (from 20 fewer to 148 more)	⊕⊕⊕◯ moderate1	CRITICAL
Change in LVESD
2	Randomised trials	Not serious	Not serious	Not serious	Not serious	None	123	114	-	SMD 0.2 lower (0.7 lower to 0.3 higher)	⊕⊕⊕⊕ high	CRITICAL

¹Imprecision associated with indirect measure of the outcome in some of the included studies.

LVEF: Left ventricular ejection fraction; CI: Confidence interval; SMD: Standardized mean difference; RR: Risk ratio; ⊕⊕⊕⊕: High level of certainty; ⊕⊕⊕◯: Moderate level of certainty; CRITICAL: Importance of outcome; AEs: Adverse events; LVESD: Left ventricular end systolic diameter; LVEDD: Left ventricular end diastolic diameter.