Cardiol Res

Cardiology Research, ISSN 1923-2829 print, 1923-2837 online, Open Access

Article copyright, the authors; Journal compilation copyright, Cardiol Res and Elmer Press Inc

Journal website http://www.cardiologyres.org

Original Article

Volume 11, Number 1, February 2020, pages 40-49

Effect of Ivabradine on Left Ventricular Diastolic Function, Exercise Tolerance and Quality of Life in Patients With Heart Failure: A Systemic Review and Meta-Analysis of Randomized Controlled Trials

Figure 3. Forest plot showing the effect of ivabradine on diastolic echocardiographic parameters compared with control in patients with HFpEF and HFrEF; change in E/A, and change in E/e’. E/e’: early diastolic mitral inflow to annular velocity ratio; E/A: early diastolic mitral inflow to late diastolic flow ratio; HFpEF: heart failure with preserved ejection fraction; HFrEF: heart failure with reduced ejection fraction; CI: confidence interval.

Figure 4. Forest plot showing the effect of ivabradine on exercise tolerance (peak VO₂ (mg/kg/min), distance on 6-min walking test (m)) compared with control in patients with HFpEF and HFrEF. VO₂: peak oxygen uptake during exercise; HFpEF: heart failure with preserved ejection fraction; HFrEF: heart failure with reduced ejection fraction; CI: confidence interval.

Figure 5. Forest plot showing the effect of ivabradine on QOL (using MLHFQ score) compared with control. HFrEF: heart failure with reduced ejection fraction; CI: confidence interval; MLHFQ: Minnesota Living with Heart Failure Questionnaire; QOL: quality of life.

Figure 6. Forest plot showing the effect of ivabradine on worsening heart failure and all-cause mortality. HFrEF: heart failure with reduced ejection fraction; CI: confidence interval.

**Table 1.** Study Characteristics of Patients With Heart Failure With Preserved Ejection Fraction (HFpEF)
Author (year)	Number of patients	Setting	Entry LVEF	Control	Mean age (yrs)	Men (%)	Mean HR at baseline (bpm)	Primary endpoint of interest	Follow-up
LVEF: left ventricular ejection fraction; yrs: years; HR: heart rate; bpm: beats per minute; E/e’: early diastolic mitral inflow to annular velocity ratio; E/A: early diastolic mitral inflow to late diastolic flow ratio; 6MWT: 6-min walk test; VO₂: peak oxygen uptake during exercise; N/A: not available.
Kosmala et al, 2013 [15]	61	Two centers	≥ 50%	Placebo	67 ± 8	N/A		E/e’, E/A, peak VO₂	7 days
Cocco et al, 2013 [16]	42	Single-center	> 50%	Digoxin	61.8 ± 4.4	48	85 ± 5	E/e’, E/A, 6MWT	3 months
Pal et al, 2015 [17]	22		≥ 50%	Placebo		N/A	N/A	E/e’, peak VO₂	2 weeks

Table 1. Study Characteristics of Patients With Heart Failure With Preserved Ejection Fraction (HFpEF)

Author (year)

Number of patients

Setting

Entry LVEF

Control

Mean age (yrs)

Men (%)

Mean HR at baseline (bpm)

Primary endpoint of interest

Follow-up

LVEF: left ventricular ejection fraction; yrs: years; HR: heart rate; bpm: beats per minute; E/e’: early diastolic mitral inflow to annular velocity ratio; E/A: early diastolic mitral inflow to late diastolic flow ratio; 6MWT: 6-min walk test; VO₂: peak oxygen uptake during exercise; N/A: not available.

Kosmala et al, 2013 [15]

Two centers

≥ 50%

Placebo

67 ± 8

N/A

E/e’, E/A, peak VO₂

7 days

Cocco et al, 2013 [16]

Single-center

> 50%

Digoxin

61.8 ± 4.4

85 ± 5

E/e’, E/A, 6MWT

3 months

Pal et al, 2015 [17]

≥ 50%

Placebo

N/A

E/e’, peak VO₂

2 weeks

**Table 2.** Study Characteristics of Patients With Heart Failure With Reduced Ejection Fraction (HFrEF)
Author (year)	Number of patients	Setting	Entry LVEF	Control	Mean age (yrs)	Men (%)	Mean HR at baseline (bpm)	Primary endpoint of interest	Follow-up
LVEF: left ventricular ejection fraction; yrs: years; HR: heart rate; E/e’: early diastolic mitral inflow to annular velocity ratio; E/A: early diastolic mitral inflow to late diastolic flow ratio; 6MWT: 6-min walk test; VO₂: peak oxygen uptake during exercise; MLHFQ: Minnesota Living with Heart Failure Questionnaire; HF: heart failure; N/A: not available.
Abdel-Salam et al, 2015 [18]	43	Single-center	< 40%	Placebo	50.8 ± 14.5	53.5	85 ± 12	MLHFQ	3 months
Villacorta et al, 2018 [19]	19		< 50%	Pyridostigmine		N/A		Peak VO₂, MLHFQ	6 months
Mansour et al, 2011 [20]	53	Single-center	< 40%	Standard therapy	49 ± 113	60	N/A	MLHFQ	3 months
Raja et al, 2018 [21]	125	Single-center	< 40%	Standard therapy	47.2 ± 15	56.9	94.9 ± 10	6MWT, MLHFQ	6 months
Sarullo et al, 2010 [22]	60	Single-center	< 40%	Placebo	52.7 ± 5.3	75		Peak VO₂	3 months
Sisakian et al, 2016 [23]	54	Single-center	< 40%	Standard therapy		81	N/A	E/A, E/e’	3 months
Volterrani et al, 2011 [24]	121	Multicenter	HF	Carvedilol	66.8 ± 9.5	N/A	77.5 ± 12.2	Peak VO₂, 6MWT, MLHFQ	3 months
Lofrano-Alves et al, 2016 [25]	26		< 40%	Placebo		N/A	N/A	E/e’, E/A	6 months
Fasullo et al, 2009 [26]	155	Single-center	< 50%	Beta-blocker				E/A	60 days
Othman et al, 2019 [27]	40	Single-center	< 40%	Beta-blockers				6MWT, MLHFQ	1 month

Table 2. Study Characteristics of Patients With Heart Failure With Reduced Ejection Fraction (HFrEF)

Author (year)

Number of patients

Setting

Entry LVEF

Control

Mean age (yrs)

Men (%)

Mean HR at baseline (bpm)

Primary endpoint of interest

Follow-up

LVEF: left ventricular ejection fraction; yrs: years; HR: heart rate; E/e’: early diastolic mitral inflow to annular velocity ratio; E/A: early diastolic mitral inflow to late diastolic flow ratio; 6MWT: 6-min walk test; VO₂: peak oxygen uptake during exercise; MLHFQ: Minnesota Living with Heart Failure Questionnaire; HF: heart failure; N/A: not available.

Abdel-Salam et al, 2015 [18]

Single-center

< 40%

Placebo

50.8 ± 14.5

53.5

85 ± 12

MLHFQ

3 months

Villacorta et al, 2018 [19]

< 50%

Pyridostigmine

N/A

Peak VO₂, MLHFQ

6 months

Mansour et al, 2011 [20]

Single-center

< 40%

Standard therapy

49 ± 113

N/A

MLHFQ

3 months

Raja et al, 2018 [21]

125

Single-center

< 40%

Standard therapy

47.2 ± 15

56.9

94.9 ± 10

6MWT, MLHFQ

6 months

Sarullo et al, 2010 [22]

Single-center

< 40%

Placebo

52.7 ± 5.3

Peak VO₂

3 months

Sisakian et al, 2016 [23]

Single-center

< 40%

Standard therapy

N/A

E/A, E/e’

3 months

Volterrani et al, 2011 [24]

121

Multicenter

Carvedilol

66.8 ± 9.5

N/A

77.5 ± 12.2

Peak VO₂, 6MWT, MLHFQ

3 months

Lofrano-Alves et al, 2016 [25]

< 40%

Placebo

N/A

E/e’, E/A

6 months

Fasullo et al, 2009 [26]

155

Single-center

< 50%

Beta-blocker

E/A

60 days

Othman et al, 2019 [27]

Single-center

< 40%

Beta-blockers

6MWT, MLHFQ

1 month