Heart failure (HF) is a clinical syndrome with enormous relevance given its constantly. Benefits of early treatment with

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1 A low percentage of patients achieve optimal β-blocker doses and optimal heart rate values with β-blocker administration. Ivabradine has been recognized not only for providing a prognostic benefit, but also for a prognostic significance with regard to the time required to achieve heart rate control, as seen in the SHIFT study [I]ntroducing and uptitrating drugs early during the vulnerable phase after hospitalization can be important for a reduction in mortality and early rehospitalization. F OCUS Benefits of early treatment with b-blockers plus ivabradine compared with b-blockers alone in patients hospitalized with heart failure by M. Anguita, F. J. Hidalgo, F. Carrasco, J. C. Castillo, J. López-Aguilera, Spain Manuel ANGUITA, MD, PhD Francisco J. HIDALGO, MD Francisco CARRASCO, MD Juan C. CASTILLO, MD, PhD José LÓPEZ-AGUILERA, MD, PhD Department of Cardiology Hospital Universitario Reina Sofía Córdoba, SPAIN Address for correspondence: Dr Manuel Anguita, Department of Cardiology, Hospital Universitario Reina Sofía, Avda. Menéndez Pidal 1, 14004, Córdoba, Spain ( manuelp.anguita.sspa@ juntadeandalucia.es) H eart rate (HR) has prognostic value in patients with heart failure (HF), reduced ejection fraction (ref), and sinus rhythm HFrEF. Current guidelines recommend a target HR below 70 beats per minute, but there is controversy about the strategy to follow. Here, we discuss our study on the effect of early coadministration of ivabradine plus b-blockers (intervention group) versus initial use of b-blockers only (control group) in HFrEF patients hospitalized with acute HF, with regard to HR and clinical and functional outcomes in the long term (follow-up reached to 3 years). Analysis included 71 consecutive patients randomized to the two treatment strategies (33, intervention; 38, control). Age and EF at admission were similar in both groups. The intervention group had lower HR at 28 days (P=0.01), a difference that remained significant at 1 and 3 years; higher EF at 1 year (P=0.002), with a trend toward a better symptomatic situation (New York Heart Association functional class, P<0.1); lower (though not statistically significant) probability of cardiovascular death at 1 year; and at 3 years, trends toward lower rates of HF readmissions (P=0.1) and of the combined end point of HF readmissions/cardiovascular death (P=0.1). No severe side effects from early administration of ivabradine were observed. Thus, early coadministration of ivabradine and b-blockers during hospital admission for acute HFrEF is feasible and safe and produces a significant decrease in HR and improvement in left ventricular systolic function. A trend toward lower long-term event rates was observed. Wider and prolonged follow-up studies are needed to determine if these findings are associated with a significant reduction in long-term clinical outcomes. Medicographia. 2018;40:47-52 Introduction Heart failure (HF) is a clinical syndrome with enormous relevance given its constantly growing prevalence and its poor prognosis. 1,2 Approximately half the HF patients have reduced left ventricular ejection fraction (HFrEF). 1 In patients with HFrEF and sinus rhythm, heart rate (HR) seems to have prognostic value. A directly proportional relationship between HF reduction with ivabradine and prognostic improvement has been observed. 3,4 Recent clinical practice guidelines have set HR target values (<70 bpm) and have included a pure heart-rate slowing drug ivabradine, a specific inhibitor of the I f -current in the sinus node, 5 in the therapeutic algorithm for treatment of patients that have already received an optimal dose of b-blockers or the maximum-tolerated dose of these drugs 6,7 and continue to have a HR greater than 70 bpm. Ivabradine has been shown to have a prognostic benefit and to improve outcomes even in patients with chronic severe systolic HF. 8 Early treatment with b-blockers plus ivabradine vs b-blockers alone in HF Anguita and others MEDICOGRAPHIA, Vol 40, No. 1,

2 Some studies have reported that there is a relationship between the reduction in HR and the use of b-blockers, but no correlation has been found with b-blocker dose Moreover, it s also known that a low percentage of patients achieve optimal b-blocker doses and optimal HR values with b-blocker administration. 12 Ivabradine has been recognized not only for providing a prognostic benefit, but also for a prognostic significance with regard to the time required to achieve HR control, as seen in the SHIFT study (Systolic Heart failure treatment with the I f inhibitor ivabradine Trial). 4 Therefore, introducing and uptitrating drugs early during the vulnerable phase after hospitalization can be important for a reduction in mortality and early rehospitalization. Current indication of ivabradine is based on the SHIFT design, but until the recent publication of the ETHIC-AHF study (Early THerapy with Ivabradine in patients with Congestive Acute Heart Failure), 13,14 there were no data about the safety and potential benefits of its use added to b-blockers during hospitalization. The aim of this article is to review the short- and long-term results of the ETHIC-AHF study and the possible role of the early administration of ivabradine in patients hospitalized for acute HF. ETHIC-AHF study design The ETHIC-AHF study, whose protocol, design, and initial results have recently been published 13 is a prospective, comparative, and randomized trial with a simple randomization strategy in which we compared the strategy recommended by the current clinical practice guidelines 6,7 ie, use of b-blockers in increasing doses, with addition of ivabradine only in those patients who, after reaching the optimal dose or the maximumtolerated dose of b-blockers, continued to have a HR above 70 bpm (control group) against the strategy of simultaneous and early starting (24-48 hours after HF admission) of b-blockers and ivabradine, with simultaneous and progressive uptitration of both drugs (intervention group). Inclusion criteria were: Hospital admission with acute HF, either de novo or decompensated. Ejection fraction less than 40% of irreversible a priori etiology. Age over 18 years. SELECTED ABBREVIATIONS AND ACRONYMS BNP CRT ETHIC-AHF HF HFrEF HR NYHA NS SHIFT B-type natriuretic peptide cardiac resynchronization therapy Early THerapy with Ivabradine in patients with Congestive Acute Heart Failure heart failure heart failure with reduced ejection fraction heart rate New York Heart Association not significant Systolic Heart failure treatment with the I f inhibitor ivabradine Trial Attainment of clinical stabilization. Heart in sinus rhythm, with a HR above 70 bpm. No previous treatment with ivabradine. Absence of serious concomitant disease that would result in a shortened life span (life expectancy of less than 6 months). Not a carrier or candidate for pacemaker implantation/resynchronization at admission (patients not considered as candidates for cardiac resynchronization therapy [CRT] at the time of admission, despite presenting with the electrocardiographic criteria, a de novo etiology, or exacerbation of less than 6 months of evolution). Not a candidate for heart transplantation, cardiac surgery, or other invasive cardiovascular procedures at admission. Possibility of follow-up for at least 1 year. Signed informed consent. Patients with a personal history of atrial fibrillation or ventricular dysfunction secondary to an acute event (eg, acute myocardial infarction, myocarditis) were excluded. Patients who met these criteria and granted informed consent were randomized within 24 to 48 hours after admission to either the control group, receiving the usual pattern of b-blockers, or to the intervention group, receiving ivabradine (at a dosage of 5 mg/12 hours) plus the b-blocker (carvedilol or bisoprolol). 14 With the goal of reaching a HR below 70 bpm (roughly 60 bpm), b-blocker doses were titrated in both groups during follow-up visits after discharge; these visits occurred at 14 days, 28 days, 4 months, 8 months, and 1 year. 14 In the intervention group, the dosage of ivabradine could be increased during follow-up visits, up to 7.5 mg/12 hours; in the control group, ivabradine could be added to b-blocker after the follow-up visit at 28 days if a patient s HR was above 70 bpm despite treatment with the optimal dosage of b-blockers (10 mg/day of bisoprolol or 25 mg/12 hours of carvedilol) or the maximum-tolerated dosage of these drugs. 14 The primary outcome of the study was heart rate at 28 days after discharge. 13,14 Secondary outcomes consisted of the evolution of HR at 4 months and 1 year, left ventricular ejection fraction, B-type natriuretic peptide (BNP) levels, New York Heart Association (NYHA) functional class, drug safety (adverse effects and withdrawal from medication due to adverse effects), and major clinical cardiac events (cardiac death and readmissions for HF) at 1 year and 3 years after discharge. 14 Patients underwent follow-up evaluation at 15 days, 28 days, 4 months, 1 year, and 3 years after discharge. 14 Main findings of the ETHIC-AHF study There were 71 patients included in the study analysis; initially, 72 patients were enrolled between November 2013 and April 2015, but one was removed early before discharge after the patient revoked consent. 14 Of the 71 remaining 33 in the intervention group and 38 in the control group all completed the planned follow-up. 14 The flowchart of patients included and excluded and the reasons for it have been pub- 48 MEDICOGRAPHIA, Vol 40, No. 1, 2018 Early treatment with b-blockers plus ivabradine vs b-blockers alone in HF Anguita and others

3 Intervention Control P-value Age (years) 66.2 ± ± 12.3 NS Men (%) NS HBP (%) NS Diabetes (%) NS Smoking (%) NS Anemia (%) NS Functional class III/IV at NS hospitalization (%) Diuretics at discharge (%) NS ACE inhibitor/arb at discharge (%) NS MRA at discharge (%) NS b-blockers at discharge (%) NS b-blocker doses* NS High (%) Medium (%) Low (%) Ejection fraction at discharge (%) 32.9 ± ± 6.1 NS BNP at discharge (pg/ml) 463 ± ± 399 NS Heart rate at admission (bpm) 87.3 ± ± 11.2 NS Heart rate at discharge (bpm) 70.1 ± ± 9.3 NS lished, 13 as well as baseline characteristics and the treatment received during hospitalization and at discharge. 13 Table I 14 summarizes the most important characteristics of both groups, showing no differences between groups. There were no significant differences in use of diuretics, angiotensin-converting enzyme (ACE) inhibitors/angiotensin II receptor blockers (ARB), or mineralocorticoid receptor antagonist (MRA). 13 HR at 28 days after hospital discharge, the primary end point of the study, was significantly lower in the intervention group (64.3±7.5 vs 70.3±9.3 bpm; P=0.01), and this difference remained significant at 4 months, 1 year (61.8±5.5 vs 68.5±9.3 bpm; P=0.01), and 3 years (data not shown). Table I. Summary of the main characteristics of the intervention (ivabradine plus b-blockers) and control groups (initially receiving b-blockers only) during hospitalization. Abbreviations: ACE, angiotensin-converting enzyme; ARB, angiotensin II receptor blocker; BNP, B-type natriuretic peptide; bpm, beats per minute; HBP, high blood pressure; MRA, mineralocorticoid receptor antagonist. After reference 14: Hidalgo et al. Int J Clin Cardiol. 2017; 4(1):093. doi: / / , Hidalgo FJ, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. intervention group had a HR rate under 70 bpm, compared with 82% in the control group (P=0.04) (Figure 2, page 50). 14 Left ventricular ejection fraction, though similar in both groups at admission and discharge, 13 was significantly higher in the intervention group at 1-year follow-up (48.2±17% vs 41.8±10%; P=0.002) (Figure 3, page 50). 14 BNP values were significantly lower in the intervention group at the 4-month follow-up visit, but the differences between groups at 1-year follow-up were not significant (300.9±117.4 vs 484.3±137 pg/ml; P=0.3). 14 There was a trend toward a lower percentage of patients in NYHA class III or IV ambulatory in the intervention group, although it did not reach statistical significance (14.8% vs 21.2%; P=0.5). 14 Figure 1 shows the HR in both groups during follow-up. 14 At 1-year follow-up, there were no differences in the percentage of patients receiving medium/high doses of b-blockers in the two groups (58% vs 60%; P=0.86), whereas 22 patients (81.5%) in the intervention group were receiving ivabradine (mean dosage, 13.2±2 mg/day; 8 patients, 5 mg/12 hours; 14 patients, 7.5 mg/12 hours) versus 11 patients (33%) in the control group (mean dosage of 10.9±1.7 mg/day; 9 patients, 5 mg/12 hours; 2 patients, 7.5 mg/12 hours; P<0.001). 14 No severe adverse effects related to b-blockers or ivabradine that would force their withdrawal were recorded; however, ivabradine was discontinued in three patients (2, control group; 1, intervention group), and its dosage was reduced (from 7.5 mg to 5 mg/12 hours) in one patient from the intervention group to allow for an increased dose of b-blocker. 14 Note that at 1-year follow-up, all patients (100%) in the Figure 1. Heart rate in the intervention (ivabradine plus b-blockers) and control (initially receiving b-blockers only) groups during follow-up. Abbreviation: bpm, beats per minute. After reference 14: Hidalgo et al. Int J Clin Cardiol. 2017;4(1):093. doi: / / , Hidalgo FJ, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Early treatment with b-blockers plus ivabradine vs b-blockers alone in HF Anguita and others MEDICOGRAPHIA, Vol 40, No. 1,

4 Figure 2. Percentage of patients in the intervention (ivabradine plus b-blockers) and control (initially receiving b-blockers only) groups with heart rate lower than 70 beats per minute. Abbreviations: bpm, beats per minute; HR, heart rate. After reference 14: Hidalgo et al. Int J Clin Cardiol. 2017;4(1):093. doi: / / , Hidalgo FJ, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. The rate of clinical events at 1-year follow-up was similar in both groups. 14 Although the probability of cardiovascular death was 26% lower in the intervention group, this difference was not statistically significant (hazard ratio, 0.74; 95% confidence interval, ; Figure 4), and the incidence of cardiovascular death or of rehospitalization due to HF was similar (Figure 4). 14 Total mortality was also similar in both groups (10.5% vs 15.5%, not significant). 14 At 3- year follow-up, patients in the ivabradine group showed a trend toward lower rates for HF readmissions (18.8% vs 28.2%; P=0.1) and for the combined end point of HF readmissions/cardiovascular death (32.3% vs 43.6%; P=0.1). During follow-up, three patients from each group received treatment by electrical devices (cardiac resynchronization therapy [CRT] or implantable cardiac defibrillator). 14 One patient in the intervention group who remained in ambulatory functional class IV despite optimal medical therapy, had severe systolic biventricular dysfunction, and was not a candidate for CRT received a successful transplant. 14 At 1- and 3- year follow-up, we did not record any severe adverse effects related to the drugs used. sinus rhythm, and the addition of ivabradine in patients who do not reach this objective (class IIa, level of evidence B). 14 However, there is no data on the usefulness of HR control in the most vulnerable stage of the disease, ie, in patients hospitalized for an episode of acute HF. The recently published ETHIC-AHF study 13,14 carried out in patients with acute HF has demonstrated the safety and efficacy of the early administration of ivabradine plus b-blockers during hospitalization, resulting in a significant reduction in HR, an increase in left ventricular ejection fraction, a reduction in BNP levels, and a trend toward a better functional class 4 months after discharge. 13,14 The results from 1- and 3-year follow-up confirm the initial short-term results. 14 HR remained significantly lower in the intervention group, which received treatment with both ivabradine and b-blockers at admission (Figure 1), even though at 1 year, both groups had a similar use of b-blockers and ivabradine. 14 Also, a significantly higher percentage of patients reached the target HR (<70 bpm) in the intervention group than in the control group (Figure 2). 14 Left ventricular ejection fraction was significantly higher in patients initially randomized to ivabradine plus b-blockers and was greater at 1 year than at 4 months (Figure 3). 14 Also, the trend toward lesser Discussion Control of HR is increasing in priority in patients with HFrEF because of improved prognosis in terms of mortality and HF events. 3,4,14 Current practice guidelines 6,7 recommend optimal doses of b-blockers (class I, level of evidence A) to achieve a HR under 70 bpm in patients with ambulatory HFrEF and Figure 3. Left ventricular ejection fraction in the intervention (ivabradine plus b-blockers) and control (initially receiving b-blockers only) groups during follow-up. After reference 14: Hidalgo et al. Int J Clin Cardiol. 2017;4(1):093. doi: / / , Hidalgo FJ, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 50 MEDICOGRAPHIA, Vol 40, No. 1, 2018 Early treatment with b-blockers plus ivabradine vs b-blockers alone in HF Anguita and others

5 Figure 4. Probability at 1-year follow-up of not suffering cardiovascular death and/or hospitalization for heart failure (left), and of not suffering cardiovascular death (right) in both treatment groups (intervention [ivabradine plus b-blockers] and control [initially receiving b-blockers only]). Abbreviations: CI, confidence interval; CV, cardiovascular; HF, heart failure; HR, heart ratio. After reference 14: Hidalgo et al. Int J Clin Cardiol. 2017;4(1):093. doi: / / , Hidalgo FJ, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. severity of symptoms persisted at 1 year. Both groups had a similar incidence of cardiovascular events, although cardiovascular death appeared lower in the ivabradine group at 1-year follow-up (not statistically significant; Figure 4); at 3-year follow-up, there was a trend toward lower rates of HF readmissions (18.8% vs 28.2%; P=0.1) and of the combined end point of HF readmissions/cardiovascular death (32.3% vs 43.6%; P=0.1; the lack of statistical significance was probably related to the small sample size). 14 This study demonstrated the safety of the combined use of ivabradine plus b-blockers early during hospitalization in patients with acute HFrEF, chronic or de novo, and showed improved control of HR in similar percentages to those reported in other studies with uptitration of b-blockers only. 9-11,14 In addition, this combination therapy appears to improve left ventricular ejection fraction, as already reported in the SHIFT study in stable patients To our knowledge, the ETHIC- AHF 13 study is the first randomized analysis on the safety and benefits of using ivabradine in this clinical context, 14 although Sargento et al previously described similar effects on HR reduction in the short term in a nonrandomized study including 10 patients, with no follow-up results. 17 Our findings support the possibility of improving treatment of patients during the vulnerable phase, a period that carries an increased risk of short- and medium-term events, as stated in the new HF guidelines. 6,14 Early and rapid uptitration of b-blockers and the concomitant addition of ivabradine during hospitalization is safe, allows early achievement of a target HR lower than 70 bpm, and is associated with a significant improvement in left ventricular ejection fraction on short- and long-term follow-up. 14 Limitations and conclusions With the limitations of a single-center study, which includes a limited number of patients (although enough for analysis of the primary end point, HR at 28 days after discharge), our results indicate that a strategy of early coadministration of ivabradine and b-blockers during the episode of decompensated HF in patients with systolic left ventricular dysfunction and who are in sinus rhythm is feasible and safe, allowing better and earlier control of HF in these patients, without entailing a reduction in the dose of b-blockers. This is associated with a significant improvement in systolic left ventricular function and a trend toward better clinical status in patients. A larger study including a greater number of patients is necessary to confirm if these findings have a favorable long-term prognostic effect. References 1. Anguita Sánchez M, Crespo Leiro MG, de Teresa Galván E, Jiménez Navarro M, Alonso-Pulpón L, Muñiz García J; PRICE Study Investigators. Prevalence of heart failure in the Spanish general population aged over 45 years. The PRICE Study. Rev Esp Cardiol. 2008;61(10): Macintyre K, Capewell S, Stewart S, et al. Evidence of improving prognosis in heart failure. Trends in case fatality in patients hospitalized between 1986 and Circulation. 2000;102(10): Böhm M, Swedberg K, Komajda M, et al; SHIFT Investigators. Heart rate as a risk factor in chronic heart failure (SHIFT): the association between heart rate and outcomes in a randomised placebo-controlled trial. Lancet. 2010; 376(9744): Early treatment with b-blockers plus ivabradine vs b-blockers alone in HF Anguita and others MEDICOGRAPHIA, Vol 40, No. 1,

6 4. Böhm M, Borer J, Ford I, et al. Heart rate at baseline influences the effect of ivabradine on cardiovascular outcomes in chronic heart failure: analysis from the SHIFT study. Clin Res Cardiol. 2013;102(1): Savelieva I, Camm AJ. I f inhibition with ivabradine: electrophysiological effects and safety. Drug Saf. 2008;31(2): Ponikowski P, Voors AA, Anker SD, et al ESC guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2016;37(27): Yancy CW, Jessup M, Bozkurt B, et al ACC/AHA/HFSA Focused update of the 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. Circulation. 2017;136(6):e137-e Borer JS, Böhm M, Ford I, et al; SHIFT Investigators. Efficacy and safety of ivabradine in patients with severe chronic systolic heart failure (from the SHIFT study). Am J Cardiol. 2014;113(3): McAlister FA, Wiebe N, Ezekowitz JA, Leung AA, Armstrong PW. Meta-analysis: b-blocker dose, heart rate reduction, and death in patients with heart failure. Ann Intern Med. 2009;150(11): Swedberg K, Komajda M, Böhm M, et al; SHIFT Investigators. Effects on outcomes of heart rate reduction by ivabradine in patients with congestive heart failure: is there an influence of beta-blocker dose? J Am Coll Cardiol. 2012;59 (22): Cullington D, Goode KM, Clark AL, Cleland JG. Heart rate achieved or betablocker dose in patients with chronic heart failure: which is the better target? Eur J Heart Fail. 2012;14(7): Maggioni AP, Dahlstrom U, Filippatos G, et al; Heart Failure Association of ESC (HFA). EURObservational Research Programme: the Heart Failure Pilot Survey (ESC-HF Pilot). Eur J Heart Fail. 2010;12(10): Hidalgo FJ, Anguita M, Castillo JC, et al. Effect of early treatment with ivabradine combined with beta-blockers versus beta-blockers alone in patients hospitalized with heart failure and reduced left ventricular ejection fraction (ETHIC- AHF): a randomized study. Int J Cardiol. 2016;217: Hidalgo FJ, Carrasco F, Castillo JC, et al. Early therapy with beta blockers plus ivabradine versus beta blockers alone in patients hospitalized with heart failure and reduced ejection fraction (ETHIC-AHF Study): results at one-year followup. Int J Clin Cardiol. 2017;4(1):093. doi: / / Swedberg K, Komajda M, Böhm M, et al; SHIFT Investigators. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. Lancet. 2010;376(9744): Tardif JC, O Meara E, Komadja M, et al. Effects of selective heart rate reduction with ivabradine on left ventricular remodelling and function: results from the SHIFT echocardiographic substudy. Eur Heart J. 2011;32(20): Sargento L, Satendra M, Longo S, Lousada N, dos Reis RP. Heart rate reduction with ivabradine in patients with acute decompensated systolic heart failure. Am J Cardiovasc Drugs. 2014;14(3): Keywords: b-blocker; combination; ETHIC-AHF; heart failure; heart rate; ivabradine 52 MEDICOGRAPHIA, Vol 40, No. 1, 2018 Early treatment with b-blockers plus ivabradine vs b-blockers alone in HF Anguita and others