Am J Cardiovasc Drugs (2014) 14:229–235 DOI 10.1007/s40256-013-0060-1
SHORT COMMUNICATION
Heart Rate Reduction with Ivabradine in Patients with Acute Decompensated Systolic Heart Failure Luis Sargento • Milan Satendra • Susana Longo Nuno Lousada • Roberto Palma dos Reis
•
Published online: 23 January 2014 Ó Springer International Publishing Switzerland 2014
Abstract Introduction In patients with acute decompensated systolic heart failure (ADSHF) high resting heart rate (HR) could be either a compensatory mechanism or contribute to worsening heart failure. The aim of this study was to evaluate, in patients with ADSHF and resting HR[70 bpm, the early (within 24 h) and late (at discharge) effects of oral administration of ivabradine on HR reduction. Methods Ten consecutive patients with ADSHF, left ventricular ejection fraction \40 % and HR [70 bpm, without other acute conditions or inotropic therapy, began open-label treatment with oral ivabradine according to a pre-established Heart Failure Unit protocol. We obtained clinical and laboratory data at four periods: admission (T0), immediately before initiation of ivabradine (T2), 24 h after initiation of ivabradine (T3), and at discharge (T4). Results Ivabradine was administered in 60 % of the patients before the second day. HR decreased 10.7 ± 7.2 bpm at T3 (p \ 0.001) and 16.3 ± 8.2 bpm at T4 (p = 0.002). The systolic blood pressure decreased at T3 (p = 0.012), returning to baseline values at T4. There was no change in diastolic and mean blood pressure. New York Heart Association (NYHA) class improvement by two levels was associated with lower HR at T4 (p = 0.033). HR and N-terminal pro-brain natriuretic peptide (Nt-ProBNP) at M. Satendra and L. Sargento contributed equally to this article. L. Sargento (&) S. Longo N. Lousada Heart Failure Unit, Cardiology Department, Pulido Valente Hospital, Lisbon North Hospital Centre, Rua Manuel Costa Silva no 7-2A, 1750-335 Lisbon, Portugal e-mail: [email protected] M. Satendra R. P. dos Reis Cardiology Department, Pulido Valente Hospital, Lisbon North Hospital Centre, Lisbon, Portugal
baseline correlated significantly [Spearman correlation coefficient (rs) = 0.789, p = 0.013]. Total Nt-ProBNP reduction correlated with the HR before (r = 0.762, p = 0.028) and after (T3: r = 0.647, p = 0.083; T4: r = 0.738, p = 0.037) ivabradine addition. Conclusion In the present cohort of patients with ADSHF and HR [70 bpm, the selective reduction of HR with oral ivabradine was safe and efficient.
1 Introduction Heart rate (HR) is a major determinant of myocardial oxygen demand, coronary blood flow, and myocardial performance in the general population [1, 2], and patients with cardiovascular diseases [3], heart failure (HF) [4], and multi-organ damage syndromes [5]. Increased HR is usual in acute decompensated systolic heart failure (ADSHF), and may act as a compensatory mechanism or be as a consequence of vasopressor amines [6]. The decrease of mortality in acute coronary syndromes depends on the achieved HR reduction in the acute setting [7–9]. The reduction of HR in ADSHF could be an important and modifiable therapeutic target. This can be achieved with the administration of b-blockers; however, there are potential adverse effects with these agents, such as negative inotropism and arterial hypotension. Ivabradine, an If inhibitor, improves event-free survival in HF patients with left ventricular (LV) systolic dysfunction and resting HR [70 bpm [10], along with LV reverse remodeling at 8 months [11], quality of life [12], and exercise capacity [13] improvement. The negative chronotropic effect of ivabradine is comparable with that of b-blockers but without negatively influencing inotropism or causing arterial hypotension [13].
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The novel aspect of ivabradine relates to its anatomic (cardiac sinus atrial node cells) and functional (If channels) selectivity and specificity [14]. Thus, it does not affect myocardial contractility, preserves cardiac output, and significantly enhances stroke volume and systolic stroke work [15]. Therefore, the selective HR reduction, without the possible adverse effects of hypotension or decreased contractility, may be strong arguments supporting its use in patients with ADSHF and tachycardia. Ivabradine therapy has demonstrated anti-ischemic and anti-angina efficiencies and a good tolerability in other acute settings, such as in patients with acute coronary syndrome [16–18] and patients with advanced HF [19, 20]. Administered by a single intravenous bolus, ivabradine reduces HR after 30 min [19, 21]. Intravenous perfusion or oral ivabradine achieves the maximum HR reduction after 4 h [15, 18, 19, 22]. This rapid and sustained action in HR could create a problem when administered to patients with ADSHF, as tachycardia may be a compensatory mechanism and HR reduction could, theoretically, lead to clinical worsening. Currently, ivabradine use in ADSHF remains off-label, leaving the full responsibility and legal liability of ivabradine effects and side effects with the prescriber. The manufacturer of ivabradine, to date, has not sought its approval for ADSHF. For this reason, our study is openlabel. The aim of this study was to evaluate, in patients with ADSHF and resting HR [70 bpm, the early (within 24 h) and late (at discharge) effects of oral administration of ivabradine on HR reduction.
2 Materials and Methods 2.1 Methods This study, conducted in our cardiac intensive care unit (CICU) between July 2010 and April 2011, was designed as an observational, open-label, longitudinal, and retrospective study with the purpose of examining the efficacy and safety of HR reduction with oral ivabradine in patients with ADSHF. The study was conducted in accordance with the ethical principles of the Helsinki Declaration and Good Clinical Practice and was approved by the local ethics committee. All patients provided written informed consent prior to study participation. 2.2 Study Population After patients’ evaluation by two senior cardiologists, ivabradine was initiated according to a pre-established clinical protocol. It was an open-label trial as ivabradine, in this setting, is an off-label therapy.
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Inclusion criteria were as follows: patients were followed up in the Heart Failure Unit (HFU) for at least 6 months and admitted to the CICU from the HFU with ADSHF, in sinus rhythm, had an LV ejection fraction \40 %, systolic blood pressure (SBP) [90 mmHg, resting HR[70 bpm, and were on optimal medical therapy for HF as considered by the European Society of Cardiology guidelines [23]. Exclusion criteria were as follows: cardiogenic shock (at any time during hospitalization), patients on inotropes (or planned inotropic therapy), acute coronary syndrome, stroke or cerebral transient ischemic attack within the previous 6 months, hemodynamically significant valvular heart disease, sick sinus syndrome, sinoatrial block and congenital long QT, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels C2.5-fold higher than the normal values at the study center (or C100 U/L), blood bilirubin C3.0 mg/dL, and creatinine C2.5 mg/dL. During this period, ivabradine was administrated to ten patients according to the above criteria. 2.3 Study Design All patients were observed by two senior cardiologists from the HFU, who decided if the patients could benefit from HR reduction with ivabradine. According to a pre-established protocol, the ivabradine standard starting dose was 5 mg twice daily. A lower dose of 2.5 mg twice daily could be considered in patients aged above 75 years. All patients were maintained with continuous monitoring of the HR in the CICU for at least 72 h. Discontinuation of the drug was allowed at any time in case of hemodynamic deterioration. No uptitration of ivabradine was allowed during the first 72 h. After 72 h, titration of ivabradine was carried out according to the following protocol: (1) uptitration to 7.5 mg twice daily if HR was not 20 % lower; (2) reduction to 2.5 mg twice daily if HR\60 bpm; or (3) otherwise maintained. 2.4 Clinical Measurements The following items were surveyed: demographics, history, and cardiovascular risk factors. We obtained the clinical and therapeutics data at four time-points: admission to the CICU (T0), just before initiation of therapy with ivabradine (T2), 24 h after initiation of therapy with ivabradine (T3), and at discharge (T4). The clinical status was classified at baseline and discharge was according to the New York Heart Association (NYHA) class. The hemodynamic parameters collected were SBP, diastolic blood pressure (DBP), mean blood pressure (MBP), HR, 24 h diuresis, and saturation of peripheral oxygen (SpO2). Analytical parameters were also obtained at T0, T2, and T4:
HR Reduction with Ivabradine in ADHF
hemoglobin, hematocrit, N-terminal pro-brain natriuretic peptide (Nt-ProBNP), urea, creatinine, glomerular filtration rate [GFR, defined using the Modification of Diet in Renal Disease (MDRD) method], sodium, potassium, AST, ALT, and blood glucose. 2.5 Objectives The primary objective of the study was to evaluate, in patients with ADSHF and resting HR [70 bpm, the early (within 24 h) and late (at discharge) effects of oral administration of ivabradine on HR reduction. The secondary objectives were to evaluate the effect of selective HR reduction: (1) on blood pressure (SBP, DBP, and MAP); (2) on Nt-ProBNP; and (3) in the relationship between HR and Nt-ProBNP. 2.6 Statistics Results are expressed as mean ± standard deviation. The temporal variation (T0–T4) of the various parameters was assessed with the Kruskall–Wallis test. Paired data were evaluated with the Paired Student t test and Wilcoxon Signed Rank Test. The between-groups variation were determined with the grouped Student t test and the Mann– Whitney test. The association between parameters was achieved with the Pearson correlation coefficient and the Spearman correlation coefficient (rs). The variation of the HR and Nt-ProBNP was calculated as [initial–final] values. All tests are two-tailed and performed using SPSSÒ software version 17 (SPSS Inc., Chicago, IL, USA).
3 Results The demographic characteristics, risk factors, and clinical and analytical parameters on admission are described in Table 1. 3.1 Ivabradine Titration On average, administration of ivabradine was started in 6.10 ± 6.6 days, with 60 % of patients having started therapy by the second day. The mean dose at discharge was 9.5 ± 2.8 mg/day. 3.2 Variation of the Vital Parameters (Table 2; Fig. 1) During the time of the study (T0–T4) there was a significant variation of the HR (p \ 0.001) and SBP (p = 0.018), without significant changes of the DBP and MBP. Before the addition of ivabradine (T0–T2) there was no significant change in vital parameters. However, 24 h after
231 Table 1 Clinical characteristics, concomitant diseases, analytical evaluation, and therapeutics at admission Age (years)
62.4 ± 17.3
Men [n (%)]
8 (80)
Days in hospital
20.4 ± 18.1
LVEF (%)
31.2 ± 9.2
NYHA class [n (%)]
III: 5 (50); IV: 5 (50)
Hypertension [n (%)]
7 (70)
LBBB [n (%)]
3 (30)
Diabetes mellitus [n (%)]
4 (40)
Hypercholesterolemia [n (%)]
4 (40)
Smoking [n (%)]
2 (20)
Hb (g/dL) Ht (%)
12.4 ± 2.4 37.0 ± 6.5
RDW (%)
14.3 ± 1.2
Nt-ProBNP (pg/mL)
7,452.6 ± 7,747.8
Urea (mg/dL)
64.8 ± 37.2
Creatinine (mg/dL)
1.48 ± 0.6
GFRMDRD (mL/min/1.73 m2)
62.9 ± 29.8
Sodium (mmol/mL)
133.6 ± 4.9
Potassium (mmol/mL)
4.5 ± 1.1
Ev Furosemide [n (%)]
10 (100)
Spironolactone [n (%)]
4 (40)
ACEi/ARA [n (%)]
7 (70)
b-Blocker [n (%)]
6 (60)
Nitrates [n (%)]
6 (60)
Digoxin [n (%)]
4 (40)
ACEi ACE inhibitor, ARA angiotensin receptor antagonist (blocker), GFRMDRD glomerular filtration rate, defined using the Modification of Diet in Renal Disease method, Hb hemoglobin, Ht hematocrit, LBBB left bundle branch block, LVEF left ventricular ejection fraction, NtProBNP N-terminal pro-brain natriuretic peptide, NYHA New York Heart Association, RDW dispersion index of the volume of erythrocytes
ivabradine administration (T2–T3), there was a significant decrease in HR (p = 0.001) and SBP (p = 0.008), without significant change in MBP and DBP. The SBP decreased at T3 in all, yet without hemodynamic deterioration. The late effect, evaluated at discharge (T4), in relation to T2 (p = 0.002) and T3 (p = 0.006) showed a progressive reduction in HR and an increase in SBP (T3–T4; p = 0.012). There was no significant change in SBP at T4 in relation to T0 and T2. The HR decreased in all patients at T3; however, in two patients it increased from T3 to T4 (Fig. 1). At T3 and T4, 50 and 80 %, respectively, of the patients had a HR \70 bpm. The average HR reduction before ivabradine addition was 5.5 ± 8.6 bpm. With ivabradine, the HR reduction achieved was 10.7 ± 7.2 bpm at T3 and 16.3 ± 8.2 bpm at T4, in relation to T2.
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Table 2 Clinical, hemodynamic, and laboratory parameters during the four time-points Parameter
No ivabradine T0
RHR (bpm) SBP (mmHg) DBP (mmHg) MBP (mmHg) Nt-ProBNP (pg/mL) Creatinine (mg/dL) Hemoglobin (g/dL) Sodium (mmol/L) NYHA class 24 h diuresis (mL) SPO2 (%)
88.3 112.6 64.7 86.9 7,452
T2 ± ± ± ± ±
11.1 21.1 6.7 12.7 7,747
82.8 113.2 62.3 87.2 4,695
± ± ± ± ±
13.9 17.4 8.3 10.6 5,490
Ivabradine addition
No ivabradine
Ivabradine addition
T3
T4
T0 vs. T2a
T2 vs. T3a
72.1 ± 8.7 105.6 ± 13.6 61.6 ± 13.8 84.0 ± 9.3 –
66.5 113.7 58.8 85.7 4,645.4
0.418 0.076 0.254 0.852 0.310
± ± ± ± ±
8.2 14.3 9.1 6.9 3,736
Baseline/ final
All timepoints
T3 vs. T4a
T0 vs. T4a
T0–T4b
0.001 0.008 0.775 0.152 –
0.006 0.012 0.237 0.430 –
\0.001 0.819 0.028 0.705 0.093
0.001 0.018 0.529 0.592 0.050
1.5 ± 0.6
1.2 ± 0.5
–
1.3 ± 0.4
0.156
–
–
0.161
0.239
12.4 ± 2.4
11.8 ± 2.0
–
12.6 ± 1.8
0.352
–
–
0.661
0.264
133.6 ± 4.9
137.2 ± 4.0
–
137.2 ± 2.5
0.130
–
–
0.07
0.272
3.5 ± 0.5 1,608 ± 1,078
– 1,411 ± 447.0
– 1,445 ± 305.0
2.1 ± 0.4 –
– 0.496
– 0.780
– –
\0.001 –
96.4 ± 9.6
99.6 ± 2.6
97.2 ± 1.4
0.682
0.287
0.541
96.9 ± 1.1
0.223
– – 0.674
DBP diastolic blood pressure, MBP mean blood pressure, Nt-ProBNP N-terminal pro-brain natriuretic peptide, NYHA New York Heart Association, RHR resting heart rate, SBP systolic blood pressure, SpO2 saturation of peripheral oxygen, T0 admission to cardiac intensive care unit, T2 just before ivabradine initiation, T3 24 h after T2, T4 discharge a Significance levels for the time-points paired comparison b Significance levels for the time effect (T0–T4)
3.3 N-Terminal Pro-Brain Natriuretic Peptide (NtProBNP) and Renal Function Variation The Nt-ProBNP decreased progressively (p = 0.05 across all three time points between T0 and T4) (Table 2). Creatinine, GFR, sodium, and hemoglobin did not vary significantly. 3.4 HR Relationship with Nt-ProBNP and Clinical Status Before ivabradine administration (T0 and T2) the HR correlated directly with Nt-ProBNP (T0: rs = 0.667, p = 0.071; T2: rs = 0.789, p = 0.013). The Nt-ProBNP value at T2 correlated with the decrease of HR 24 h after ivabradine addition (r = 0.796, p = 0.018). The total decrease of Nt-ProBNP (T0–T4) correlated with the HR at baseline (T2: r = 0.762, p = 0.028), T3 (r = 0.647, p = 0.083), and T4 (r = 0.738, p = 0.037). When analyzing the total variation in two intervals (T0–T2 and T2–T4), we found no significant correlation between the decrease in Nt-ProBNP and HR in T0–T2, but it was significant for the last interval (rs = 0.857, p = 0.014). At discharge, the NYHA class decreased by one or two levels in 70 and 30 % of patients, respectively. The subgroup whose NYHA class decreased by two levels had lower HR values at discharge (69.7 ± 7.6 vs. 59.0 ± 3.6
bpm; p = 0.033). The total HR reduction with ivabradine (T2–T4; 16.1 ± 6.6 vs. 16.6 ± 4.2 bpm) was similar in both subgroups. Analyzing this in two time intervals (T2– T3 and T3–T4), in the first interval there was no difference in HR reduction; however, in the latter interval there was a significant variation in the HR reduction (3.2 ± 3.7 vs. 11.0 ± 1.7 bpm; p = 0.010) between the two subgroups of patients. 3.5 Safety None of the patients suspended ivabradine. There were no reports of hemodynamic deterioration because of symptomatic bradycardia or other adverse effects.
4 Discussion This pilot study shows that in patients with ADSHF and HR [70 bpm, ivabradine safely decreases the HR 24 h after its initiation, continuing to decrease it until hospital discharge. HR is a major determinant of myocardial oxygen consumption and energy utilization. Moreover, it modulates cardiac afterload [24], reduces diastolic perfusion time, and may trigger ischemic events and arrhythmias. Patients with ADSHF often present with increased HR, which can be a compensatory mechanism to improve cardiac output, a
HR Reduction with Ivabradine in ADHF
Fig. 1 Resting heart rate (a), systolic blood pressure (b) and mean blood pressure (c), by patient, during the four time-points (T0— admission to the cardiac intensive care unit; T2—just before ivabradine initiation; T3—24 h after ivabradine initiation; T4— hospital discharge). MBP mean blood pressure, RHR resting heart rate, SBP systolic blood pressure
consequence of vasopressor amines [6] or a contributing factor for clinical deterioration. The reduction in HR is possibly one of the most important energy-saving maneuvers in cardiogenic shock and multiorgan failure [25]. Thus, in the present work, the high HR is exclusively related to the ADSHF physiopathology. Ivabradine, an If inhibitor, reduces intrinsic pacemaker activity in the sinoatrial node without affecting myocardial contractility, preserving cardiac output and the stroke
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volume [14]. Ivabradine is presently not indicated in the treatment of cardiogenic shock and acute myocardial infarction. Already used for other cardiovascular disorders, ivabradine provides better oxygenation of the heart subject to stress, inducing a rapid, sustained and dose-dependent reduction of HR at rest and during exercise [13, 26] without significant effect on LV contraction [27]. These properties, associated with the unloading of the left ventricle [24], result in an increase of the stroke volume. Because of all these beneficial effects, ivabradine may play a role in ADSHF. Some studies have been published in the literature which investigated the future potential of this drug in critically ill patients [26]. In the context of primary angioplasty, ivabradine was safely administrated, contributing to a positive remodeling [17, 18]. In patients with advanced HF, the intravenous administration decreased HR by a maximum of 27 % after 4 h, increasing the stroke volume and preserving cardiac output [20]. These were achieved despite a significant decrease in the DBP. In critical patients with low cardiac output syndrome after cardiopulmonary bypass and catecholamine-induced tachycardia, ivabradine was administered orally, was successfully absorbed and reached the maximum effect on HR within 4 h [22]. This rapid and sustained HR reduction [18, 20, 22] with oral or intravenous administration of ivabradine could be a problem in patients with ADSHF, as tachycardia might be a compensatory mechanism. This could be more pronounced in patients with ADSHF without external causes for tachycardia. Our cohort of patients is included in this setting. Nevertheless, the therapeutic window is wide and may be enough to avoid complications [28, 29]. The present study includes a cohort of patients with severe systolic HF followed up in our HFU who were hospitalized with ADSHF. As ivabradine is not currently approved in this setting, this therapy should be considered off-label. We rejected patients in shock or planned inotropic therapy, as those are different clinical settings. All patients were on intravenous furosemide, with high values of Nt-ProBNP and sinus HR[70 bpm. Ivabradine was administrated in 60 % of the patients before the second day. The HR decreased 10.7 ± 7.2 bpm 24 h after ivabradine administration. The maximum HR decrease was 16.3 ± 8.2 bpm, at discharge. A HR\70 bpm was achieved in 50 and 80 % of patients at T3 and discharge, respectively. Thus, the decrease in HR was rapid but sustained. SBP decreased in all patients at T3, without hemodynamic deterioration. There was no significant variation of the MBP and DBP, which explain the hemodynamic stability. A similar pattern of variation for the DBP and MBP has previously been described [20]. The clinical status, classified by NYHA class, was associated with the HR and its variation. Those who improved the NYHA class by two levels had lower HR at
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discharge and greater reduction in HR from T3 to T4. However, the NYHA class is a subjective classification, although improvement in clinical status is very important in HF. The ability to feel better and perform common daily activities improves not only physical activity, but favors a good mental state [30, 31]. Several important correlations between HR and NtProBNP were determined. Before ivabradine addition, NtProBNP and HR correlated significantly, as previously described in outpatients with chronic HF [32]. Moreover, the total Nt-ProBNP decrease (T0–T4) was associated with the HR before and after ivabradine addition. However, this correlation was only significant for the Nt-ProBNP variation within the T2–T4 period. Thus, the determined correlation between HR and Nt-ProBNP decrease is mainly explained by its association after ivabradine addition, as in outpatients with chronic HF [32]. These correlations could have been influenced by diuretic therapy. We did not analyze weight variation; however, the 24 h diuresis was used to monitor diuretic efficacy, which had no significant variation. HR modulates cardiac afterload in chronic HF [24], and the selective HR reduction improves total arterial compliance, reducing effective arterial elastance, which improves ventricular-arterial coupling [24]. This modulating effect of ivabradine could contribute to and explain the association of HR with Nt-ProBNP. The major limitation of this study was the small number of patients; however, it is a pilot study in this setting. The openlabel design of the trial is compulsory as it is an off-label indication. The single location limits generalization, but allows greater control of the study. The number of patients taking b-blockers is lower than expected for chronic HF, but could be associated with the progressive nature of the decompensation. The low proportion of patients taking spironolactone was possibly associated with the low GFR. We do not report weight change due to technical difficulties in patients in class IV; instead, we opted for reporting 24 h diuresis. The clinical status of patients was only measured by NYHA class; quality of life and dyspnea scores could have been used. A series of non-invasive hemodynamic monitoring with echocardiography could have given us more information about the effect of HR reduction in cardiac output. It is suggested that all of these parameters should be considered in future studies. Despite the many constraints of this small study, it is one of the first reports of the off-label utilization of ivabradine in patients with ADSHF.
5 Conclusion In the present cohort of patients with ADSHF and HR [70 bpm, the selective reduction of HR with oral
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ivabradine was safe and efficient. Moreover, HR had a significant association with Nt-ProBNP and NYHA class. Declaration The authors were fully responsible for all content and editorial decisions and received no financial support or other form of compensation related to the development of this manuscript. The opinions expressed in the manuscript are those of the authors, and Servier Laboratories had no influence on the contents. Disclosures No external funding was used in the conduct of this study. The authors (LS, MS, SL, NL, RPR) have no potential conflicts of interest that might be relevant to the content of this manuscript.
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235 23. McMurray JJ, Adamopoulos S, Anker SD, et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2012;33 (14):1787–847. 24. Reil JC, Tardif JC, Ford I, Lloyd SM, O’Meara E, Komajda M, Borer JS, Tavazzi L, Swedberg K, Bo¨hm M. Selective heart rate reduction with ivabradine unloads the left ventricle in heart failure patients. J Am Coll Cardiol. 2013;62(21):1977–85. 25. Post F, Mu¨nzel T. Ivabradine—a new therapeutic option for cardiogenic shock? Herz. 2009;34:224–9. 26. Riccioni G. Ivabradine: an intelligent drug for the treatment of ischemic heart disease. Molecules. 2012;17(11):13592–604. 27. Rognoni A, Bertolazzi M, Maccio` S, Rognoni G. Ivabradine: cardiovascular effects. Cardiovasc Drug Discov. 2009;4:61–6. 28. De Santis V, Vitale D, Santoro A, Magliocca A, Porto AG, Nencini C, Tritapepe L. Ivabradine: potential clinical applications in critically ill patients. Clin Res Cardiol. 2013;102(3):171–8. 29. Borer JS, Le Heuzey JY. Characterization of the heart rate-lowering action of ivabradine, a selective I(f) current inhibitor. Am J Ther. 2008;15(5):461–73. 30. Ekman I, Chassany O, Komajda M, Bo¨hm M, Borer JS, Ford I, Tavazzi L, Swedberg K. Heart rate reduction with ivabradine and health related quality of life in patients with chronic heart failure: results from the SHIFT study. Eur Heart J. 2011;32(19): 2395–404. 31. Riccioni G, Prencipe G, Benvenuto A, Masciocco L, Ventra S, Rizzo U, Russi C, Speziale G. Ivabradine improves all aspects of quality of life assessed with the 36-item short form health survey in subjects with chronic ischemic heart disease compared with beta-blockers. Pharmacology. 2013;91:35–8. 32. Sargento L, Satendra M, Longo S, et al. Early NT-proBNP decrease with ivabradine in ambulatory patients with systolic heart failure. Clin Cardiol. 2013;365:677–82.
SHORT COMMUNICATION
Heart Rate Reduction with Ivabradine in Patients with Acute Decompensated Systolic Heart Failure Luis Sargento • Milan Satendra • Susana Longo Nuno Lousada • Roberto Palma dos Reis
•
Published online: 23 January 2014 Ó Springer International Publishing Switzerland 2014
Abstract Introduction In patients with acute decompensated systolic heart failure (ADSHF) high resting heart rate (HR) could be either a compensatory mechanism or contribute to worsening heart failure. The aim of this study was to evaluate, in patients with ADSHF and resting HR[70 bpm, the early (within 24 h) and late (at discharge) effects of oral administration of ivabradine on HR reduction. Methods Ten consecutive patients with ADSHF, left ventricular ejection fraction \40 % and HR [70 bpm, without other acute conditions or inotropic therapy, began open-label treatment with oral ivabradine according to a pre-established Heart Failure Unit protocol. We obtained clinical and laboratory data at four periods: admission (T0), immediately before initiation of ivabradine (T2), 24 h after initiation of ivabradine (T3), and at discharge (T4). Results Ivabradine was administered in 60 % of the patients before the second day. HR decreased 10.7 ± 7.2 bpm at T3 (p \ 0.001) and 16.3 ± 8.2 bpm at T4 (p = 0.002). The systolic blood pressure decreased at T3 (p = 0.012), returning to baseline values at T4. There was no change in diastolic and mean blood pressure. New York Heart Association (NYHA) class improvement by two levels was associated with lower HR at T4 (p = 0.033). HR and N-terminal pro-brain natriuretic peptide (Nt-ProBNP) at M. Satendra and L. Sargento contributed equally to this article. L. Sargento (&) S. Longo N. Lousada Heart Failure Unit, Cardiology Department, Pulido Valente Hospital, Lisbon North Hospital Centre, Rua Manuel Costa Silva no 7-2A, 1750-335 Lisbon, Portugal e-mail: [email protected] M. Satendra R. P. dos Reis Cardiology Department, Pulido Valente Hospital, Lisbon North Hospital Centre, Lisbon, Portugal
baseline correlated significantly [Spearman correlation coefficient (rs) = 0.789, p = 0.013]. Total Nt-ProBNP reduction correlated with the HR before (r = 0.762, p = 0.028) and after (T3: r = 0.647, p = 0.083; T4: r = 0.738, p = 0.037) ivabradine addition. Conclusion In the present cohort of patients with ADSHF and HR [70 bpm, the selective reduction of HR with oral ivabradine was safe and efficient.
1 Introduction Heart rate (HR) is a major determinant of myocardial oxygen demand, coronary blood flow, and myocardial performance in the general population [1, 2], and patients with cardiovascular diseases [3], heart failure (HF) [4], and multi-organ damage syndromes [5]. Increased HR is usual in acute decompensated systolic heart failure (ADSHF), and may act as a compensatory mechanism or be as a consequence of vasopressor amines [6]. The decrease of mortality in acute coronary syndromes depends on the achieved HR reduction in the acute setting [7–9]. The reduction of HR in ADSHF could be an important and modifiable therapeutic target. This can be achieved with the administration of b-blockers; however, there are potential adverse effects with these agents, such as negative inotropism and arterial hypotension. Ivabradine, an If inhibitor, improves event-free survival in HF patients with left ventricular (LV) systolic dysfunction and resting HR [70 bpm [10], along with LV reverse remodeling at 8 months [11], quality of life [12], and exercise capacity [13] improvement. The negative chronotropic effect of ivabradine is comparable with that of b-blockers but without negatively influencing inotropism or causing arterial hypotension [13].
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The novel aspect of ivabradine relates to its anatomic (cardiac sinus atrial node cells) and functional (If channels) selectivity and specificity [14]. Thus, it does not affect myocardial contractility, preserves cardiac output, and significantly enhances stroke volume and systolic stroke work [15]. Therefore, the selective HR reduction, without the possible adverse effects of hypotension or decreased contractility, may be strong arguments supporting its use in patients with ADSHF and tachycardia. Ivabradine therapy has demonstrated anti-ischemic and anti-angina efficiencies and a good tolerability in other acute settings, such as in patients with acute coronary syndrome [16–18] and patients with advanced HF [19, 20]. Administered by a single intravenous bolus, ivabradine reduces HR after 30 min [19, 21]. Intravenous perfusion or oral ivabradine achieves the maximum HR reduction after 4 h [15, 18, 19, 22]. This rapid and sustained action in HR could create a problem when administered to patients with ADSHF, as tachycardia may be a compensatory mechanism and HR reduction could, theoretically, lead to clinical worsening. Currently, ivabradine use in ADSHF remains off-label, leaving the full responsibility and legal liability of ivabradine effects and side effects with the prescriber. The manufacturer of ivabradine, to date, has not sought its approval for ADSHF. For this reason, our study is openlabel. The aim of this study was to evaluate, in patients with ADSHF and resting HR [70 bpm, the early (within 24 h) and late (at discharge) effects of oral administration of ivabradine on HR reduction.
2 Materials and Methods 2.1 Methods This study, conducted in our cardiac intensive care unit (CICU) between July 2010 and April 2011, was designed as an observational, open-label, longitudinal, and retrospective study with the purpose of examining the efficacy and safety of HR reduction with oral ivabradine in patients with ADSHF. The study was conducted in accordance with the ethical principles of the Helsinki Declaration and Good Clinical Practice and was approved by the local ethics committee. All patients provided written informed consent prior to study participation. 2.2 Study Population After patients’ evaluation by two senior cardiologists, ivabradine was initiated according to a pre-established clinical protocol. It was an open-label trial as ivabradine, in this setting, is an off-label therapy.
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Inclusion criteria were as follows: patients were followed up in the Heart Failure Unit (HFU) for at least 6 months and admitted to the CICU from the HFU with ADSHF, in sinus rhythm, had an LV ejection fraction \40 %, systolic blood pressure (SBP) [90 mmHg, resting HR[70 bpm, and were on optimal medical therapy for HF as considered by the European Society of Cardiology guidelines [23]. Exclusion criteria were as follows: cardiogenic shock (at any time during hospitalization), patients on inotropes (or planned inotropic therapy), acute coronary syndrome, stroke or cerebral transient ischemic attack within the previous 6 months, hemodynamically significant valvular heart disease, sick sinus syndrome, sinoatrial block and congenital long QT, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels C2.5-fold higher than the normal values at the study center (or C100 U/L), blood bilirubin C3.0 mg/dL, and creatinine C2.5 mg/dL. During this period, ivabradine was administrated to ten patients according to the above criteria. 2.3 Study Design All patients were observed by two senior cardiologists from the HFU, who decided if the patients could benefit from HR reduction with ivabradine. According to a pre-established protocol, the ivabradine standard starting dose was 5 mg twice daily. A lower dose of 2.5 mg twice daily could be considered in patients aged above 75 years. All patients were maintained with continuous monitoring of the HR in the CICU for at least 72 h. Discontinuation of the drug was allowed at any time in case of hemodynamic deterioration. No uptitration of ivabradine was allowed during the first 72 h. After 72 h, titration of ivabradine was carried out according to the following protocol: (1) uptitration to 7.5 mg twice daily if HR was not 20 % lower; (2) reduction to 2.5 mg twice daily if HR\60 bpm; or (3) otherwise maintained. 2.4 Clinical Measurements The following items were surveyed: demographics, history, and cardiovascular risk factors. We obtained the clinical and therapeutics data at four time-points: admission to the CICU (T0), just before initiation of therapy with ivabradine (T2), 24 h after initiation of therapy with ivabradine (T3), and at discharge (T4). The clinical status was classified at baseline and discharge was according to the New York Heart Association (NYHA) class. The hemodynamic parameters collected were SBP, diastolic blood pressure (DBP), mean blood pressure (MBP), HR, 24 h diuresis, and saturation of peripheral oxygen (SpO2). Analytical parameters were also obtained at T0, T2, and T4:
HR Reduction with Ivabradine in ADHF
hemoglobin, hematocrit, N-terminal pro-brain natriuretic peptide (Nt-ProBNP), urea, creatinine, glomerular filtration rate [GFR, defined using the Modification of Diet in Renal Disease (MDRD) method], sodium, potassium, AST, ALT, and blood glucose. 2.5 Objectives The primary objective of the study was to evaluate, in patients with ADSHF and resting HR [70 bpm, the early (within 24 h) and late (at discharge) effects of oral administration of ivabradine on HR reduction. The secondary objectives were to evaluate the effect of selective HR reduction: (1) on blood pressure (SBP, DBP, and MAP); (2) on Nt-ProBNP; and (3) in the relationship between HR and Nt-ProBNP. 2.6 Statistics Results are expressed as mean ± standard deviation. The temporal variation (T0–T4) of the various parameters was assessed with the Kruskall–Wallis test. Paired data were evaluated with the Paired Student t test and Wilcoxon Signed Rank Test. The between-groups variation were determined with the grouped Student t test and the Mann– Whitney test. The association between parameters was achieved with the Pearson correlation coefficient and the Spearman correlation coefficient (rs). The variation of the HR and Nt-ProBNP was calculated as [initial–final] values. All tests are two-tailed and performed using SPSSÒ software version 17 (SPSS Inc., Chicago, IL, USA).
3 Results The demographic characteristics, risk factors, and clinical and analytical parameters on admission are described in Table 1. 3.1 Ivabradine Titration On average, administration of ivabradine was started in 6.10 ± 6.6 days, with 60 % of patients having started therapy by the second day. The mean dose at discharge was 9.5 ± 2.8 mg/day. 3.2 Variation of the Vital Parameters (Table 2; Fig. 1) During the time of the study (T0–T4) there was a significant variation of the HR (p \ 0.001) and SBP (p = 0.018), without significant changes of the DBP and MBP. Before the addition of ivabradine (T0–T2) there was no significant change in vital parameters. However, 24 h after
231 Table 1 Clinical characteristics, concomitant diseases, analytical evaluation, and therapeutics at admission Age (years)
62.4 ± 17.3
Men [n (%)]
8 (80)
Days in hospital
20.4 ± 18.1
LVEF (%)
31.2 ± 9.2
NYHA class [n (%)]
III: 5 (50); IV: 5 (50)
Hypertension [n (%)]
7 (70)
LBBB [n (%)]
3 (30)
Diabetes mellitus [n (%)]
4 (40)
Hypercholesterolemia [n (%)]
4 (40)
Smoking [n (%)]
2 (20)
Hb (g/dL) Ht (%)
12.4 ± 2.4 37.0 ± 6.5
RDW (%)
14.3 ± 1.2
Nt-ProBNP (pg/mL)
7,452.6 ± 7,747.8
Urea (mg/dL)
64.8 ± 37.2
Creatinine (mg/dL)
1.48 ± 0.6
GFRMDRD (mL/min/1.73 m2)
62.9 ± 29.8
Sodium (mmol/mL)
133.6 ± 4.9
Potassium (mmol/mL)
4.5 ± 1.1
Ev Furosemide [n (%)]
10 (100)
Spironolactone [n (%)]
4 (40)
ACEi/ARA [n (%)]
7 (70)
b-Blocker [n (%)]
6 (60)
Nitrates [n (%)]
6 (60)
Digoxin [n (%)]
4 (40)
ACEi ACE inhibitor, ARA angiotensin receptor antagonist (blocker), GFRMDRD glomerular filtration rate, defined using the Modification of Diet in Renal Disease method, Hb hemoglobin, Ht hematocrit, LBBB left bundle branch block, LVEF left ventricular ejection fraction, NtProBNP N-terminal pro-brain natriuretic peptide, NYHA New York Heart Association, RDW dispersion index of the volume of erythrocytes
ivabradine administration (T2–T3), there was a significant decrease in HR (p = 0.001) and SBP (p = 0.008), without significant change in MBP and DBP. The SBP decreased at T3 in all, yet without hemodynamic deterioration. The late effect, evaluated at discharge (T4), in relation to T2 (p = 0.002) and T3 (p = 0.006) showed a progressive reduction in HR and an increase in SBP (T3–T4; p = 0.012). There was no significant change in SBP at T4 in relation to T0 and T2. The HR decreased in all patients at T3; however, in two patients it increased from T3 to T4 (Fig. 1). At T3 and T4, 50 and 80 %, respectively, of the patients had a HR \70 bpm. The average HR reduction before ivabradine addition was 5.5 ± 8.6 bpm. With ivabradine, the HR reduction achieved was 10.7 ± 7.2 bpm at T3 and 16.3 ± 8.2 bpm at T4, in relation to T2.
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Table 2 Clinical, hemodynamic, and laboratory parameters during the four time-points Parameter
No ivabradine T0
RHR (bpm) SBP (mmHg) DBP (mmHg) MBP (mmHg) Nt-ProBNP (pg/mL) Creatinine (mg/dL) Hemoglobin (g/dL) Sodium (mmol/L) NYHA class 24 h diuresis (mL) SPO2 (%)
88.3 112.6 64.7 86.9 7,452
T2 ± ± ± ± ±
11.1 21.1 6.7 12.7 7,747
82.8 113.2 62.3 87.2 4,695
± ± ± ± ±
13.9 17.4 8.3 10.6 5,490
Ivabradine addition
No ivabradine
Ivabradine addition
T3
T4
T0 vs. T2a
T2 vs. T3a
72.1 ± 8.7 105.6 ± 13.6 61.6 ± 13.8 84.0 ± 9.3 –
66.5 113.7 58.8 85.7 4,645.4
0.418 0.076 0.254 0.852 0.310
± ± ± ± ±
8.2 14.3 9.1 6.9 3,736
Baseline/ final
All timepoints
T3 vs. T4a
T0 vs. T4a
T0–T4b
0.001 0.008 0.775 0.152 –
0.006 0.012 0.237 0.430 –
\0.001 0.819 0.028 0.705 0.093
0.001 0.018 0.529 0.592 0.050
1.5 ± 0.6
1.2 ± 0.5
–
1.3 ± 0.4
0.156
–
–
0.161
0.239
12.4 ± 2.4
11.8 ± 2.0
–
12.6 ± 1.8
0.352
–
–
0.661
0.264
133.6 ± 4.9
137.2 ± 4.0
–
137.2 ± 2.5
0.130
–
–
0.07
0.272
3.5 ± 0.5 1,608 ± 1,078
– 1,411 ± 447.0
– 1,445 ± 305.0
2.1 ± 0.4 –
– 0.496
– 0.780
– –
\0.001 –
96.4 ± 9.6
99.6 ± 2.6
97.2 ± 1.4
0.682
0.287
0.541
96.9 ± 1.1
0.223
– – 0.674
DBP diastolic blood pressure, MBP mean blood pressure, Nt-ProBNP N-terminal pro-brain natriuretic peptide, NYHA New York Heart Association, RHR resting heart rate, SBP systolic blood pressure, SpO2 saturation of peripheral oxygen, T0 admission to cardiac intensive care unit, T2 just before ivabradine initiation, T3 24 h after T2, T4 discharge a Significance levels for the time-points paired comparison b Significance levels for the time effect (T0–T4)
3.3 N-Terminal Pro-Brain Natriuretic Peptide (NtProBNP) and Renal Function Variation The Nt-ProBNP decreased progressively (p = 0.05 across all three time points between T0 and T4) (Table 2). Creatinine, GFR, sodium, and hemoglobin did not vary significantly. 3.4 HR Relationship with Nt-ProBNP and Clinical Status Before ivabradine administration (T0 and T2) the HR correlated directly with Nt-ProBNP (T0: rs = 0.667, p = 0.071; T2: rs = 0.789, p = 0.013). The Nt-ProBNP value at T2 correlated with the decrease of HR 24 h after ivabradine addition (r = 0.796, p = 0.018). The total decrease of Nt-ProBNP (T0–T4) correlated with the HR at baseline (T2: r = 0.762, p = 0.028), T3 (r = 0.647, p = 0.083), and T4 (r = 0.738, p = 0.037). When analyzing the total variation in two intervals (T0–T2 and T2–T4), we found no significant correlation between the decrease in Nt-ProBNP and HR in T0–T2, but it was significant for the last interval (rs = 0.857, p = 0.014). At discharge, the NYHA class decreased by one or two levels in 70 and 30 % of patients, respectively. The subgroup whose NYHA class decreased by two levels had lower HR values at discharge (69.7 ± 7.6 vs. 59.0 ± 3.6
bpm; p = 0.033). The total HR reduction with ivabradine (T2–T4; 16.1 ± 6.6 vs. 16.6 ± 4.2 bpm) was similar in both subgroups. Analyzing this in two time intervals (T2– T3 and T3–T4), in the first interval there was no difference in HR reduction; however, in the latter interval there was a significant variation in the HR reduction (3.2 ± 3.7 vs. 11.0 ± 1.7 bpm; p = 0.010) between the two subgroups of patients. 3.5 Safety None of the patients suspended ivabradine. There were no reports of hemodynamic deterioration because of symptomatic bradycardia or other adverse effects.
4 Discussion This pilot study shows that in patients with ADSHF and HR [70 bpm, ivabradine safely decreases the HR 24 h after its initiation, continuing to decrease it until hospital discharge. HR is a major determinant of myocardial oxygen consumption and energy utilization. Moreover, it modulates cardiac afterload [24], reduces diastolic perfusion time, and may trigger ischemic events and arrhythmias. Patients with ADSHF often present with increased HR, which can be a compensatory mechanism to improve cardiac output, a
HR Reduction with Ivabradine in ADHF
Fig. 1 Resting heart rate (a), systolic blood pressure (b) and mean blood pressure (c), by patient, during the four time-points (T0— admission to the cardiac intensive care unit; T2—just before ivabradine initiation; T3—24 h after ivabradine initiation; T4— hospital discharge). MBP mean blood pressure, RHR resting heart rate, SBP systolic blood pressure
consequence of vasopressor amines [6] or a contributing factor for clinical deterioration. The reduction in HR is possibly one of the most important energy-saving maneuvers in cardiogenic shock and multiorgan failure [25]. Thus, in the present work, the high HR is exclusively related to the ADSHF physiopathology. Ivabradine, an If inhibitor, reduces intrinsic pacemaker activity in the sinoatrial node without affecting myocardial contractility, preserving cardiac output and the stroke
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volume [14]. Ivabradine is presently not indicated in the treatment of cardiogenic shock and acute myocardial infarction. Already used for other cardiovascular disorders, ivabradine provides better oxygenation of the heart subject to stress, inducing a rapid, sustained and dose-dependent reduction of HR at rest and during exercise [13, 26] without significant effect on LV contraction [27]. These properties, associated with the unloading of the left ventricle [24], result in an increase of the stroke volume. Because of all these beneficial effects, ivabradine may play a role in ADSHF. Some studies have been published in the literature which investigated the future potential of this drug in critically ill patients [26]. In the context of primary angioplasty, ivabradine was safely administrated, contributing to a positive remodeling [17, 18]. In patients with advanced HF, the intravenous administration decreased HR by a maximum of 27 % after 4 h, increasing the stroke volume and preserving cardiac output [20]. These were achieved despite a significant decrease in the DBP. In critical patients with low cardiac output syndrome after cardiopulmonary bypass and catecholamine-induced tachycardia, ivabradine was administered orally, was successfully absorbed and reached the maximum effect on HR within 4 h [22]. This rapid and sustained HR reduction [18, 20, 22] with oral or intravenous administration of ivabradine could be a problem in patients with ADSHF, as tachycardia might be a compensatory mechanism. This could be more pronounced in patients with ADSHF without external causes for tachycardia. Our cohort of patients is included in this setting. Nevertheless, the therapeutic window is wide and may be enough to avoid complications [28, 29]. The present study includes a cohort of patients with severe systolic HF followed up in our HFU who were hospitalized with ADSHF. As ivabradine is not currently approved in this setting, this therapy should be considered off-label. We rejected patients in shock or planned inotropic therapy, as those are different clinical settings. All patients were on intravenous furosemide, with high values of Nt-ProBNP and sinus HR[70 bpm. Ivabradine was administrated in 60 % of the patients before the second day. The HR decreased 10.7 ± 7.2 bpm 24 h after ivabradine administration. The maximum HR decrease was 16.3 ± 8.2 bpm, at discharge. A HR\70 bpm was achieved in 50 and 80 % of patients at T3 and discharge, respectively. Thus, the decrease in HR was rapid but sustained. SBP decreased in all patients at T3, without hemodynamic deterioration. There was no significant variation of the MBP and DBP, which explain the hemodynamic stability. A similar pattern of variation for the DBP and MBP has previously been described [20]. The clinical status, classified by NYHA class, was associated with the HR and its variation. Those who improved the NYHA class by two levels had lower HR at
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discharge and greater reduction in HR from T3 to T4. However, the NYHA class is a subjective classification, although improvement in clinical status is very important in HF. The ability to feel better and perform common daily activities improves not only physical activity, but favors a good mental state [30, 31]. Several important correlations between HR and NtProBNP were determined. Before ivabradine addition, NtProBNP and HR correlated significantly, as previously described in outpatients with chronic HF [32]. Moreover, the total Nt-ProBNP decrease (T0–T4) was associated with the HR before and after ivabradine addition. However, this correlation was only significant for the Nt-ProBNP variation within the T2–T4 period. Thus, the determined correlation between HR and Nt-ProBNP decrease is mainly explained by its association after ivabradine addition, as in outpatients with chronic HF [32]. These correlations could have been influenced by diuretic therapy. We did not analyze weight variation; however, the 24 h diuresis was used to monitor diuretic efficacy, which had no significant variation. HR modulates cardiac afterload in chronic HF [24], and the selective HR reduction improves total arterial compliance, reducing effective arterial elastance, which improves ventricular-arterial coupling [24]. This modulating effect of ivabradine could contribute to and explain the association of HR with Nt-ProBNP. The major limitation of this study was the small number of patients; however, it is a pilot study in this setting. The openlabel design of the trial is compulsory as it is an off-label indication. The single location limits generalization, but allows greater control of the study. The number of patients taking b-blockers is lower than expected for chronic HF, but could be associated with the progressive nature of the decompensation. The low proportion of patients taking spironolactone was possibly associated with the low GFR. We do not report weight change due to technical difficulties in patients in class IV; instead, we opted for reporting 24 h diuresis. The clinical status of patients was only measured by NYHA class; quality of life and dyspnea scores could have been used. A series of non-invasive hemodynamic monitoring with echocardiography could have given us more information about the effect of HR reduction in cardiac output. It is suggested that all of these parameters should be considered in future studies. Despite the many constraints of this small study, it is one of the first reports of the off-label utilization of ivabradine in patients with ADSHF.
5 Conclusion In the present cohort of patients with ADSHF and HR [70 bpm, the selective reduction of HR with oral
L. Sargento et al.
ivabradine was safe and efficient. Moreover, HR had a significant association with Nt-ProBNP and NYHA class. Declaration The authors were fully responsible for all content and editorial decisions and received no financial support or other form of compensation related to the development of this manuscript. The opinions expressed in the manuscript are those of the authors, and Servier Laboratories had no influence on the contents. Disclosures No external funding was used in the conduct of this study. The authors (LS, MS, SL, NL, RPR) have no potential conflicts of interest that might be relevant to the content of this manuscript.
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