Best of heart failure

38 Novel drugs for heart rate control in heart failure Agata Bielecka-Dabrowa 1 & Stephan von Haehling 2 & Jacek Rysz 3 & Maciej Banach 1 Published online: 28 March 2018 # Springer Science+Business Media, LLC, part of Springer Nature 2018 Abstract In patients with heart failure, increased sympathetic activity is associated with a positive chronotropic stimulation leading to accelerated resting heart rate. Elevated heart rate (HR) is a risk factor for cardiovascular events, both in the general population and in patients with heart failure. Ivabradine is a pure HR-lowering agent, and it does not affect myocardial contractility, blood pressure, intracardiac conduction, or ventricular repolarization. In clinical trials such as BEAUTIFUL, CARVIVA HF, SHIFT, and INTENSIFY in patients with systolic left ventricular dysfunction, heart rate reduction with ivabradine brought positive outcomes. However, the results of the recent meta-analysis are rather neutral. In a diabetes mouse model of heart failure with preserved ejection fraction (HFpEF), selective heart rate reduction by I f inhibition improved vascular stiffness, left ventricular (LV) contractility, and diastolic function. However, EDIFY (Effect of ivabradine in patients with heart rate with preserved ejection fraction) trial show that the use of ivabradine in patients with HFpEF is not supported. The further clinical trials investigating the use of ivabradine in heart failure should be carried out. Keywords Heart failure . Ivabradine . Heart rate Heart failure burden Chronic heart failure (HF) is highly prevalent and affects roughly 2 – 3% of the population in industrialized countries. It is associated with significant morbidity and mortality. HF progresses even in the setting of current evidenced-based ther- apies with many patients ultimately requiring mechanical sup- port and/or heart transplantation for survival [ 1 , 2 ]. Patients with HF are categorized on the basis of underlying left ven- tricular ejection fraction (LVEF) into HF with preserved ejec- tion fraction (HFpEF), reduced LVEF (HFrEF), and mid- range LVEF (HFmrEF) [ 3 ]. While LVEF is the most commonly used surrogate marker of left ventricular (LV) systolic function, the implementation of two-dimensional echocardiography in estimating this pa- rameter imposes certain caveats on current HF classification [ 1 – 3 ]. In HFrEF, pharmacotherapy with inhibitors of the re- nin – angiotensin aldosterone system (RAAS) and sympathetic nervous system improves survival, reduces morbidity, and has been the mainstay of medical management [ 4 , 5 ]. Beta- blockers have reduced morbidity and mortality beyond what is achieved with RAAS antagonists alone. Additional benefits of these drugs in the management of chronic HF include im- proved left ventricular remodeling and reduction in sudden deaths. These benefits seem to be linked, at least in part, to their heart rate-lowering properties [ 4 , 5 ]. Heart rate as a therapeutic target Resting heart rate (HR) is central to cardiac output and is influenced by changes occurring in numerous diseases. Resting HR is the heart rate with the subject being quiet or inactive. HR can be viewed as an overall reflection of the status of the cardiovascular system, and it is an indicator of autonomic nervous system activity and body metabolic rate. HR can be affected by many factors, for example, physical fitness, psychological status, diet, drugs, co-morbidities, and * Agata Bielecka-Dabrowa agatbiel7@poczta.onet.pl Maciej Banach maciejbanach@aol.co.uk 1 Department of Hypertension, Chair of Nephrology and Hypertension, Medical University of Lodz, Zeromskiego 113, 90-549 Lodz, Poland 2 Department of Cardiology and Pneumology, University of Göttingen Medical Center, Göttingen, Germany 3 Department of Nephrology, Hypertension and Family Medicine, Chair of Nephrology and Hypertension, Medical University of Lodz, Zeromskiego St. 113, 90-549 Lodz, Poland Heart Failure Reviews (2018) 23:517 – 525 https://doi.org/10.1007/s10741-018-9696-x recommended to be increased after 2 – 4 weeks as tolerated to reach the target 97/103 mg twice daily. Sacubitril-valsartan should not be given concomitantly with ACE inhibitors due to risk for angioedema, and ACE inhibitor treatment should be stopped for 36 h before starting treatment with ARNI. For patients with eGFR < 30 mL/min/1.73 m 2 or moderate hepatic impairment, the starting dosage of ARNI is 24/26 mg twice daily and ARNI is not recommended for patients with severe hepatic impairment [ 38 ]. With the results of the PARADIGM trial, several new rec- ommendations have been added to the 2017 Focused Update HF Guidelines. First, for patients who are not treated with ACE inhibitors or angiotensin receptor blockers, the initial strategy of RAS inhibition can include either an ACE inhibitor or ARB or ARNI. The guidelines specify that the clinical strategy of inhibition of the RAS with ACE inhibitors (level of evidence: A), or ARBs (level of evidence: A), or ARNI (level of evidence: B – R) in conjunction with evidence-based beta-blockers and aldosterone antagonists in selected patients is recommended for patients with chronic HFrEF to reduce morbidity and mortality [ 1 •• ]. In the 2017 Focused Update of HF Guidelines, in patients with chronic symptomatic HFrEF NYHA class II or III who tolerate an ACE inhibitor or ARB, replacement by an ARNI is recommended to further reduce morbidity and mortality [ 1 •• , 36 •• ]. In those patients who are being considered to be switched to ARNI from ACE inhibitors, it is very important to n te that ARNI should not be administered concomitantly with ACE inhibitors or within 36 h of the last dose of an ACE inhibitor due to angioedema risk [ 1 •• , 35 ]. Simila ly, ARNI sh uld not be administered to patients with a history of angio- edema [ 1 •• ]. I the studies with combined neprilysin and ACE inhibition, blacks and smokers were particularly at risk for angioedema [ 35 ]. It is helpful for patients receivi ARNI to be educat d about rec gnition of the symptoms of angio de- ma and to alert health care provi ers against concomitant pre- scription of ACE inhibitors with ARNI. In a phase II trial in patients with heart failure with pre- served ejection fraction, LCZ696 reduced NT-proBNP to a greater extent than did valsartan at 12 weeks and was well tole rated [ 39 ]. The efficac y and safety of ARNI in acute de- compensated HF, in advanced HF patients with NYHA class IV symptoms, or in patients with HF-PEF is unclear at this time and is being tested in large-scale trials. Ivabradine Ivabradine is a spec fic and sel ctive inhib to of the If io channel. If ion channel (the funny current) is highly expressed in spontaneously active cardiac regions, such as the sinoatrial node, the AV node, and the Purkinje fibers. The funny current is a mixed Na/K current that activates upon hyperpolarization at voltages in the diastolic range, and controls the rate of spontaneous activity of sinoatrial myocytes, hence the cardiac rate [ 40 ]. In the Systolic HF treatment with the If inhibitor Ivabradine Trial (SHIFT), among HFrEF with normal sinus rhythm and a baseline heart rate ≥ 70 bpm despite treatment with beta-blockers, ivabradine treatment was associated with reduction in combined end point of cardiovascular death or HF hospitalization when compared against placebo [ 41 •• ]. Interestingly, though the trial intended to recruit patients on target or maximally tolerated doses of β -blockers, 26% of patients were on full-dose β -blockers. The treatment effect reflected a reduction only in the risk of hospitalization for worsening HF; there was no benefit observed for the mortality component of the primary end point [ 41 •• ]. Patients enrolled included a small number with paroxysmal atrial fibrillation (< 40% of the time) but otherwise in sinus rhythm and a small number experiencing ventricular pacing but with a predomi- nant sinus rhythm [ 41 •• ]. Ivabradine patients had higher rates of symptomatic bradycardia, atrial fibrillation, and visual side effects (phosphenes) compared to placebo [ 41 •• ]. According to the FDA drug label, ivabradine is approved to reduce hospi- talization risk for worsening HF in patients with stable, symp- tomatic chronic HF with LVEF ≤ 35% in sinus rhythm with resting HR of ≥ 70 bpm or higher and on maximally tolerated doses of beta-blockers and is contraindicated for patients with acute decompensated HF, BP < 90/50 mmHg, patients with sick sinus syndrome, sin atrial, or third-degree AV block [ 42 ]. In the 2017 Focused Update of HF Guid lines, ivabradine is identified as a treatment that can be be eficial to reduce HF hospitalizati n for patients with symptomatic (NYHA class II and III) stable chronic HFrEF (LVEF ≤ 35%) who are receiv- ing guideline-directed medical treatment, including a beta- blocker at maxi um tolerated dos , and who are in sinu rhythm with a he rt rate of ≥ 70 bpm t rest (class IIa recom- mendation, with lev l of evidence: B – R). It should be noted that t r commendation does ot entail a statement regarding mortality benefit. Contr ry to the ESC Guidelines [ 43 ], in the 2017 AHA/ACC Focused Update of HF Guideli es, there is no recommendation for ivabradin i beta-blocker i tolerant patients [ 1 •• ]. SHIFT trial was not designed to examine the efficacy of ivabradine in patients intolerant to beta-blockers. Efficacy and benefit of ivabradine in beta-blocker intolerant patients need to be tested in future trials. The current treatment strategies for management of patients with HF and reduced EF are summarized in Figs. 1 and 2 . Update on the Treatment of HFpEF Unfortunately, there are no treatment strategies with proven benefit to reduce mortality in patients with HF with preserved EF. Current treatment strategies target treatment of the underly- ing etiology for HF-pEF and comorbidities. Thus, most of the recommendations that were present in 2013 AHA/ACC HF 39 Page 4 of 9 Curr Cardiol Rep (2018) 20: 39

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