Advances in the management of heart failure: the role of ivabradine

Figures & data

Table 1 Types of heart failure with prognostic relevance of resting heart rate (sinus rhythm) and role of the pacemaker current inhibitor ivabradine

Role of heart rate/ivabradine	HFrEF chronic stable	HFpEF chronic stable	Acute/decompensated HF	Post-cardiac transplantation	Peripartum CM	Shock and MODS	ROSC after OHCA
Heart rate is prognostically relevant	Yes	Yes	Yes	?	Yes	Yes	Yes
Ivabradine reduces heart rate	Yes	Yes	Yes	Yes	Yes	Yes	?
Ivabradine improves prognosis	Yes	?	?	?	?	?	?
Ivabradine approved for use in EU/USA	Yes	No	No	No	No	No	No
Combination of ivabradine + beta-blocker feasible	Yes	Yes	Yes	?	Yes	?	?

Note: For patients with HFmrEF, no prospective trials with ivabradine are yet available.

Abbreviations: CM, cardiomyopathy; EU, European Union; HF, heart failure; HFmrEF, heart failure with mild-range ejection fraction; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; MODS, multiple organ dysfunction syndrome; OHCA, out-of-hospital cardiac arrest; ROSC, return of spontaneous circulation.

Table 2 Prognostic relevance of resting heart rate in chronic systolic heart failure in sinus rhythm

Patients with sinus rhythm + NYHA II–IV + LVEF ≤ 35%	SHIFT study^Citation27		Registry data^Citation30
	Placebo group: guideline therapy (without ivabradine), 2.5-year follow-up, 3,261 patients		Guideline therapy (without ivabradine), 5-year follow-up, 443 patients
Heart rate	< 75/min	≥ 75/min	< 75/min	≥ 75/min
Patients (% of total)	35.7%	64.3%	47%	53%
Primary end point: death or hospital admission for worsening heart failure	21% (RR 1.57; p < 0.0001)	33%	12% (RR 2.25; p < 0.01)	27%
Secondary end point: mortality	11% (RR 1.55; p = 0.0166)	17%	2% (RR 4.5; p < 0.05)	9%

Notes: SHIFT study:²⁷ data are given from patients of the placebo group (sinus rhythm ≥ 70/min; LVEF ≤ 35%; NYHA II–IV) under standard heart failure treatment including beta-blocker and excluding ivabradine. Of the total patients, 64.3% had a resting heart rate ≥ 75/min, with a higher value of the primary end point and the secondary end point “mortality” than those with a resting heart rate < 75/min. Registry data:³⁰ data are given from patients from outpatient clinics (sinus rhythm; LVEF ≤ 35%; NYHA II–IV), with standard heart failure treatment including beta-blocker and excluding ivabradine. Of the total patients, 53% had a resting heart rate ≥ 75/min, with a higher value of the primary end point and the secondary end point “mortality” than those with a resting heart rate < 75/min.

Abbreviations: LVEF, left ventricular ejection fraction; NYHA, New York Heart Association; RR, relative risk.

Figure 1 Effects of endotoxin on pacemaker current I_f (HCN channels) and adrenergic pacemaker current I_f stimulation in human atrial cardiomyocytes.

Notes: Endotoxin not only inhibits I_f but also intensifies beta-adrenoceptor-mediated stimulation of I_f.³⁶ I_f inhibition by endotoxin is not an unspecific effect, as the L-type calcium current is not inhibited by endotoxin. ⇑ indicates stimulation and ⇓ indicates inhibition.
Abbreviations: AC, adenylyl cyclase; cAMP, cyclic adenosine monophosphate; Gi, inhibitory G protein; Gs, stimulatory G protein; HCN, hyperpolarization-activated cyclic nucleotide-gated; I_Ca,T, T-type calcium current; I_Ca,L, L-type calcium current; I_f, “funny” current; I_K, potassium current.

Table 3 Therapeutic effects of heart rate reduction by ivabradine in heart failure patients with systolic dysfunction and sinus rhythm ≥ 75/min – data from the SHIFT

In patients with systolic heart failure (sinus rhythm; NYHA II–IV; EF < 35%; f >/= 75/min; follow-up 2.5 years)
Ivabradine treatment achieves
Heart failure hospitalization	↓ 30% (p < 0.0001)
Cardiovascular mortality	↓ 17% (p = 0.0166)
Heart failure mortality	↓ 39% (p < 0.0006)
Best effect
f < 60/min or heart rate reduction > 10/min after 28 days

Note: Data from the SHIFT study.²⁷

Abbreviations: EF, ejection fraction; f, heart rate; NYHA, New York Heart Association.

Table 4 Hemodynamic effects of intravenously applied ivabradine in patients with advanced heart failure

Variable	Baseline	1 h	4 h	24 h	p
HR	93 ± 8	81 ± 7	68 ± 9	82 ± 11	<0.01
CI	2.2 ± 0.6	2.3 ± 0.5	2.5 ± 0.5	2.5 ± 0.5	0.149
SV	44 ± 11	51 ± 12	66 ± 17	53 ± 12	< 0.01
LVSW	39 ± 13	43 ± 14	58 ± 20	45 ± 17	< 0.01
RVSW	12 ± 5	13 ± 7	17 ± 9	14 ± 8	< 0.01
SAP	103 ± 7	101 ± 9	103 ± 12	100 ± 11	0.848
DAP	71 ± 6	65 ± 4	64 ± 10	63 ± 6	< 0.01
MAP	82 ± 6	78 ± 6	77 ± 11	76 ± 9	0.098
PASP	36 ± 11	37 ± 11	44 ± 15	40 ± 13	< 0.01
PADP	21 ± 7	20 ± 7	20 ± 8	20 ± 8	0.92
PAMP	27 ± 8	27 ± 8	29 ± 10	29 ± 9	0.18
PAWP	19 ± 4	18 ± 5	18 ± 5	18 ± 6	0.8
RAP	7 ± 5	8 ± 6	9 ± 5	9 ± 5	< 0.01
SVR	1,576 ± 374	1,426 ± 334	1,334 ± 420	1,340 ± 381	0.176
TPVR	571 ± 222	539 ± 195	566 ± 297	548 ± 195	0.663

Note: The p values are for the prespecified contrasts between baseline and 3, 4, 6, 8, and 24 h of Table 2 of De Ferrari GM, Mazzuero A, Agnesina L, et al. Favourable effects of heart rate reduction with intravenous administration of ivabradine in patients with advanced heart failure. Eur J Heart Fail. 2008;10(6):550–555.⁵⁷

Abbreviations: CI, cardiac index (L ×min⁻¹×m⁻²); DAP, diastolic arterial pressure (mm Hg); HR, heart rate (min⁻¹); LVSW, left ventricular systolic work (g); MAP, mean arterial pressure (mm Hg); PADP, pulmonary arterial diastolic pressure (mm Hg); PAMP, pulmonary arterial mean pressure (mm Hg); PASP, pulmonary arterial systolic pressure (mm Hg); PAWP, pulmonary artery wedge pressure (mm Hg); RAP, right atrial pressure (mm Hg); RVSW, right ventricular systolic work (g); SAP, systolic arterial pressure (mm Hg); SV, stroke volume (mL); SVR, systemic vascular resistance (dyn×s×cm⁻⁵); TPVR, total pulmonary vascular resistance (dyn×s×cm⁻⁵); h, hours.

Table 5 Health-related quality of life in elderly heart failure patients (A) in comparison to community-dwelling elderly (B), and impact of heart failure medication – ivabradine (C, D) vs. beta-blocker (E, F) – on health-related quality of life

Medical outcome	A: heart failure patients (n = 781), mean ± SD	B: community-dwelling elderly (n = 781), mean ± SD	p value: A vs. B	Medical outcome	C: IVA (n = 110), T0 mean	D: IVA (n = 110), T1 mean	p value: C vs. D	E: beta-bloc kers (n = 111), T0 mean	F: beta-bloc kers (n = 111), TI mean	p value: E vs. F
Physical functioning	35 ± 26	67 ± 27	< 0.001	Physical functioning	63.5	77.2	0.001	64.5	72.3	0.01
Role limitations physical	19 ± 34	66 ± 41	< 0.001	Physical role	63.8	78.9	0.001	65.2	74.2	0.01
Bodily pain	66 ± 33	79 ± 22	< 0.001	Body pain	65.4	77.6	0.001	64.7	64.5	0.5
General health perceptions	44 ± 18	60 ± 19	< 0.001	General health	57.2	69.6	0.001	59.1	63.2	0.03
Vitality	40 ± 24	64 ± 19	< 0.001	Vitality	58.2	66.5	0.01	58.4	62.1	0.44
Social functioning	54 ± 31	79 ± 24	< 0.001	Social functioning	56.3	64.2	0.01	59.2	60.5	0.92
Role limitations emotional	51± 45	77±37	< 0.001	Emotional role	55.8	65.3	0.01	59.4	59.8	0.85
Mental health	66 ± 23	75 ± 17	< 0.001	Mental health	55.2	61.3	0.001	55.7	57.1	0.01
Perceived health change	26 ± 24	46 ± 18	< 0.001	Physical component summaries	44.5	49.2	0.01	43.2	45.2	0.52
Well-being	6.3 ± 1.8	7.2 ± 1.4	< 0.001	Mental component summaries	49.7	53.5	0.01	49.9	50.1	0.80
Depression				Heart rate (b.p.m.)	72	63	0.001	72	67	0.01
Depressive symptomsa	39%	21%	< 0.001
Depression scaleb	15 ± 10	10 ± 9	< 0.001

Notes: Columns 1–4: comparison of quality of life – as assessed by the Medical Outcome. Study 36-item General Health Survey (RAND-36) – in 781 patients with heart failure with 781 community-dwelling elderly. Modified from Lesman-Leegte et al.¹¹⁷ Columns 5–11: quality of life improvement – as documented by the SF-36 questionnaire – by ivabradine and beta-blockers in comparison in heart failure patients.

a Center for Epidemiological Studies-Depression scale ≥ 16.¹¹⁷

b Center for Epidemiological Studies-Depression scale.¹¹⁷ The bolding is to show those medical outcomes with a significant improvement by ivabradine, but no significant improvement by beta-blocker. Data in columns 1–4 are from Lesman-Lesman-Leegte I, Jaarsma T, Coyne JC, Hillege HL, van Veldhuisen DJ, Sanderman R. Quality of life and depressive symptoms in the elderly: a comparison between patients with heart failure and age- and gender-matched community controls. J Card Fail. 2009;15(1):17–23.¹¹⁷ and columns 5–11 are from Riccioni G, Masciocco L, Benvenuto A, et al. Ivabradine improves quality of life in subjects with chronic heart failure compared to treatment with β-blockers: results of a multicentric observational APULIA study. Pharmacology. 2013;92(5–6):276–280.¹¹⁹

Abbreviations: IVA, ivabradine; SD, standard deviation.

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