Best of heart failure

44 contemporary clinical practice (featuring multiple background drugs) who can be titrated to target beta-blocker doses seems to be in the range of 20 to 40% [ 31 ]. Hyperpolarization-activated cyclic nucleotide-gated channel inhibitors Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels play important roles both in the control of HR and neuronal excitability. HCN channels open on hyperpolariza- tion voltage, permeate to potassium and sodium, and generate an inward current, which is modulated by intracellular cyclic adenosine monophosphate (cAMP). In different cardiac pa- thologies, dysfunctional HCN channels have been suggested to be a direct cause of rhythm disorders. HCN channel gain- of-function in atrial fibrillation, ventricular hypertrophy, and failure might help enhance ectopic electrical activity and pro- mote arrhythmogenesis [ 32 ]. Novel compounds with enhanced selectivity for cardiac HCN channel isoforms are being studied as potential candidates for new drug development. Ivabradine is the first HCN channel inhibitor being clinically approved in 2005 for the treatment of chronic stable angina pectoris and HF. Ivabradine is a selective HR-reducing drug that works only in sinus rhythm. It acts by inhibiting the so-called funny current (I f ) in sinus node cells through the blockade of the I f channel (Fig. 1 ). The current across the I f channel is a mixed sodium – potassi- um current, and the I f channel is activated by hyperpolarization and regulated by direct binding of cAMP [ 33 ]. The cAMP di- rectly modulates the HCN channel by increasing the likelihood of channel opening during diastole; in this way, the diastolic depolarization slope becomes steeper and faster, leading to an increase in HR [ 34 , 35 ]. I f inhibition by ivabradine not only induces a selective reduction of resting HR but also attenuates tachycardia due to sympathetic stimulation [ 35 ]. Ivabradine is a pure resting HR-lowering agent, and it does not affect myocar- dial contractility, blood pressure, intracardiac conduction, or ven- tricular repolarization [ 36 – 38 ]. Notably, ivabradine is more ac- tive as the HR increases (when channels are more often open). When the HR is lower, ivabradine has minimal effects, because it is not able to effectively penetrate the hyperpolarization- activated cyclic nucleotide-gated channel responsible for I f [ 37 , 38 ]. Ivabradine has no effects on blood pressure, coronary and peripheral vascular resistance, and myocardial activity because I f expression is highly specific to the sinoatrial node. Compared to beta-blockers and calcium channel antagonists, ivabradine does not have any negative inotropic effect on myocardial tissue [ 39 ]. Other substances with a similar mechanism of action are being investigated. YM758 investigated and owned by Astellas Pharma is a novel I f channel inhibitor that has an inhibitory action for I f current and shows a strong and specific activ ity, selectively lowering HR and decreasing oxygen consumption by cardiac muscle. As such, it is useful as a preventive and/or treating agent for diseases of the circulatory system, such as ischemic heart diseases, HF, and arrhythmia. In clinical trials, it has been reported that the I f channel inhibitors zatebradine and ivabradine reduce HR without concomitant negative inotropic or hypotensive effects [ 40 – 43 ]. Ivabradine in clinical trials in patients with left ventricular systolic dysfunction In recent years, a large number of trials have been performed to evaluate the benefits of ivabradine as a selective HR-reducing Fig. 1 The mechanism of action of ivabradine. Ivabradine within SA node selectively blocks the HCN channel, inhibits the If current, slows diastolic depolarization, and lowers heart rate. HCN channel hyperpolarization-activated cyclic nucleotide-gated; If current inward flow of positively charged ions that initiates the spontaneous diastolic depolarization phase, modulating heart rate; SA node sinoatrial node Heart Fail Rev (2018) 23:517 – 525 519 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 note 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 ]. Similarly, ARNI should not be administered to patients with a history of angio- edema [ 1 •• ]. In the studies with combined neprilysin and ACE inhibition, blacks and smokers were particularly at risk for angioedema [ 35 ]. It is helpful for patients receiving ARNI to be educated about recognition of the symptoms of angioede- ma and to alert health care providers 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 tolerated [ 39 ]. The efficacy and safety of ARNI in acute de- compensa ed 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 specific and selective inhibitor of the If ion 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 o f the primary end point [ 41 •• ]. Patien ts 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, sinoatrial, or third-degree AV block [ 42 ]. In the 2017 Focused Update of HF Guidelines, ivabradine is identified as a treatment that can be beneficial to reduce HF hospitalization 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 maximum tolerated dose, and who are in sinus rhythm with a heart rate of ≥ 70 bpm at rest (class IIa recom- mendation, with level of evidence: B – R). It should be noted that the recommendation does not entail a statement regarding mortality benefit. Contrary to the ESC Guidelines [ 43 ], in the 2017 AHA/ACC Focused Update of HF Guidelines, there is no recommendation for ivabradine in beta-blocker intolerant 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 blockers. Beta-blockers possess strong negative inotropic ef- f t, and th y can unfavorably modify the hemodynamic pro- file of inotropic agents [ 37 , 68 – 70 ]; thus, they seem not to be uitable as rate-controlling age ts in multiple organ dysfunc- ion (MODS) pati nts. Ivabradine lowers HR, reduces diastol- ic depolarization slope, and is ot active o sympathetic path- ways, thus avoiding any interference with in tropic amines. Ivabradine could cou teract the adverse effects of elevated HR in MODS l wering myocardial oxygen con umption, in- creas ng diastolic coro ary perfusion, and acting on the nega- tive force – freq ency relationship of the fai ing he rt. Hoke nd colleagues [ 71 ] in a pr spective observational study i 89 pati nts with MODS found that HR t the time of MODS diagnosis is an independent r sk factor for mortality. Twenty- eight-day mortality was 32 and 61% in patients with HR < 90 bpm and H > 90 bpm, respectively. However, in the study by Nuding et al., the umber of critically ill patie ts with MODS and a si us rhythm of at least 90 bpm that experienced a HR reduction of at least 10 bpm did not differ significantly betwe n the ivabradine and the control groups [ 72 ]. The mo er te but significant reduction in HR by 7 bpm did not affect hemodynam- ics or sease severi y [ 72 ]. The results of the MODI(f)Y trial are needed to assess the utility of ivabradine in MODS. Summary Among patients with systolic HF, the dose to which a beta- block r c n be titrated is dependent on patient -m rbidities and other demographics. Based on ac ual data, if an increase of the d se of the beta-blocke in patients with HFrEF can be achieved and results in lowering the heart r te below 70 bpm, therapy with beta-block r alone is appropriate. If this goal is ot achieva e clinically, the addition of ivabradine will result i a r uction in the risk of future cardiovascular events. At present, there is insuffic ent evidence to justify the us of iv bra ine in HFpEF. Based on the results of EDIFY study, perhaps, it sh uld e a sessed the potential utility of ivabradine in HFpEF patients with a mitral valve flo velocity pattern of impaired LV relaxation, pseudo-normalization not in restriction [ 73 ]. There re also groups of patie ts in which ivabradine is a drug o hoice like p ople with psoriasis where beta-block rs ar contraindicated. In our opinion, ivabradine could be also the best option as rate-controlling agent in pa- ents who n ed ino ropic mine th rapy. We have positive experience with ivabradine in management of patients with cardiogenic shock. We also see a perspective for ivabradine use in conditions where it is important to reduce heart rate without blood pressure lowering like for example inappropri- ate sinus tachy ardia or postural orthostat c tac ycardia yn- drome. Further clinical tri l investi ating the use of ivabr dine in HF should be c rried out w th optimal tr atment of the patient popul tion in order to identify the subgrou f patients who respond to ivabradine. Besides, it is necessary to explore head to head comparisons f ivabradine and beta-blockers in l rge-scale trials with longer follow-up periods. Compliance with ethic l standards Conflict of interest The authors declare that they have no conflicts of interest. References 1. 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