Best of heart failure

43 contemporary clinical practice (featuring drugs) who can be titrated to target beta- be in the range of 20 to 40% [ 31 ]. Hyperpolarization-activated c nucleotide-gated channel inh Hyperpolarization-activated cyclic nuc channels play important roles both in t neuronal excitability. HCN channels o tion voltage, permeate to potassium and an inward current, which is modulated adenosine monophosphate (cAMP). In thologies, dysfunctional HCN channels to be a direct cause of rhythm disorder of-function in atrial fibrillation, ventric failure might help enhance ectopic elect mote arrhythmogenesis [ 32 ]. Novel compounds with enhanced selec channel isoforms are being studied as p new drug development. Ivabradine is t inhibitor being clinically approved in 20 chronic stable angina pectoris and HF. Iv HR-reducing drug that works only in si inhibiting the so-called funny current (I through the blockade of the I f channel (Fi The current across the I f channel is a um current, and the I f channel is activate and regulated by direct binding of cAM rectly modulates the HCN channel by in of channel opening during diastole; in t depolarization slope becomes steeper an 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 recommended to be in reach the target 97/10 should not be given c to risk for angioedema, stopped for 36 h bef patients with eGFR < impairment, the starti daily and ARNI is not hepatic impairment [ 3 With the results of t ommendations have b HF Guidelines. First, ACE inhibitors or an strategy of RAS inhibit or ARB or ARNI. T strategy of inhibition of evidence: A), or A (level of evidence: B – beta-blockers and aldo is recommended for p morbidity and mortalit In the 2017 Focuse with chronic symptom tolerate an ACE inhibit recommended to furth 36 •• ]. In those patie switched to ARNI fro to note that ARNI sho with ACE inhibitors or inhibitor due to angio should not be administ edema [ 1 •• ]. In the stu inhibition, blacks and angioedema [ 35 ]. It is be educated about rec ma and to alert health scription of ACE inhi In a phase II trial i served ejection fractio greater extent than di tolerated [ 39 ]. The eff compensated HF, in a IV symptoms, or in p time and is being teste Ivabradine Ivabradine is a specifi channel. If ion channel in spontaneously activ node, the AV node, an is a mixed Na/K curre at voltages in the dia 39 Page 4 of 9 to ivabradine may have beneficial effects in these patients, as lower levels of E/e ’ and NT-proBNP suggest reduced LV fill- ing pressures and parameters of submaximal exercise capacity were improved compared with those of beta-blockade [ 58 ]. In another randomized study in 61 patients with HFpEF, short-term treatment with ivabradine increased exercise ca- pacity, with a contribution from improved LV filling pressure response to exercise as reflected by the ratio of peak early diastolic mitral flow velocity to peak early diastolic mitral annular velocity [ 59 ]. However, the results of the studies were ambiguous. In the study of Pal et al., ivabradine compared with placebo signifi- cantly worsened the change in peak V0 2 in the HFpEF cohort ( − 2.1 vs 0.9 mL kg − 1 min − 1 ; p = 0.003) and significantly re- duced submaximal exercise capacity, as determined by the oxygen uptake efficiency slope [ 60 ]. The proof-of-concept EDIFY study (prEserveD left ventricular ejection fraction chronic HF with ivabradine studY) examined whether HR reduction with ivabradine improves diastolic function and ex- ercise capacity and reduces NT-proBNP concentration in pa- tients with HFpEF [ 61 ]. After 8 months of treatment, no evi- dence of improvement was found in any of the three co- primary endpoints. HR reduction with ivabradine did not show a beneficial effect on cardiac filling pressures (E/e ′ ), exercise capacity (6 min walk test — 6MWT), and plasma NT-proBNP concentrations. The study showed that a decrease in HR (of about 13 bpm in the ivabradine group) was associ- ated with longer LV filling time with significant increases in peak early filling velocity. However, these changes were not associated with improvements in LV relaxation (no significant increase in mean e ′ ). Therefore, E/e ′ was not reduced, reflecting no improvement in LV filling [ 61 ]. There was no change in LV mass or in arterial – ventricular coupling assessed by the Ea/Ees ratio. The authors explained the failure to demonstrate any benefit of ivabradine in HFpEF patients by the fact that the population enrolled had rather ad- vanced HFpEF with extensive myocardial fibrosis that allowed only a poor response to pharmacological intervention (subjects were too sick to benefit) [ 61 ]. In cases of extensive fibrosis with predominant restriction and no or minimal stroke volume re- serve, cardiac output is entirely dependent on HR. Also, the hypothesis that lowering HR would facilitate an increase in filling time in stiff ventricles and as a result induce a reverse remodeling was not verified. EDIFY does not support the con- cept that HR reduction is beneficial in HFpEF. This differs from findings in HFrEF, in which the SHIFT study demonstrated significant improvements in cardiovascular outcomes and an anti-remodeling effect as a result of ivabradine treatment, in- cluding when HFrEF was associated with severe diastolic dys- function [ 51 , 52 , 62 ]. One of several potential explanations of this difference might be connected to different patterns of myo- cardial remodeling arising from their different pathophysiolog- ical mechanisms in HFpEF and HFrEF [ 54 , 63 ]. Meta-analysis with ivabra ine in patients with heart failure Recently, Kang et al. performed a meta-analysis of eight ra - domized controlled clinical studies (with 40,357 participants); three of which used ivabradine versus placebo (36,069 partici- pants), and five other studies ivabradine versus beta-blockers (4288 participants). The authors aimed to investigate whether ivabradine reduces resting HR, cardiovascul r disease (CVD) mortality, and all-cause mortality than placebo or beta-blockers in randomized controlled trials [ 64 ]. The change of resting HR from baseline to endpoint was 8 to 16 bpm in th ivabradine groups, 1 to 8 bpm in the placebo groups, and 4 to 24 bpm in the beta-blockers groups. In ivabradine versus placebo, the re- duced risks of CVD mortality and all-cause morbidity wer not significant (risk ratio [RR] 1.02; 95% confiden e interval [CI] 0.91 – 1.14, p = 0.737; RR 1.00, 95% CI 0.92 – 1.09, p = 0.992, respectively). CVD and all-cause morbidity were similar for ivabradine versus beta-blockers (RR 1.04; 95% CI 0.80 – 1.37, p = 0.752; RR 1.17, 95% CI 0.53 – 2.60, p = 0.697, respectively) [ 64 ]. In this meta-analysis, ivabradine had a neutral effect sug- gesting that a pure resting HR-lowering agent does not reduce CVD and all-cause mortality. These meta-analysis dat were based on published studies and reports i different CVD opu- lations, and the authors could not provide detailed analysis to show that ivabradine would provide a possibl trend f i - proved survival in the HF population with t e cutoff of HR > 70/min. The authors noticed that ivabradine improved HF mor- tality with placebo (3 vs 5%), but it did not further decrease CVD mortality and all-cause mortality comp r to placebo i the same HF population [ 64 ]. Considering that ivabradine in this meta-analysis reduced only 2% HF death rate as compared to placebo, it is necessary in several large sample trials to prove the 2% value and significant in real world. The primary end- point of the SHIFT trial was the composite of cardiovascular death or hospital admission for worsening HF, and the effect was driven mainly by hospital admissions for worsening HF. In that situation, when patients are admitted to the hospital, follow-up is ended, so we can only know the effects of ivabradine on cardiovascular mortality when the patients die before the first hospitalization for worsening HF. It r mains unknown how the increase in the risk of atrial fibr llation oc- currence in patients treated with ivabradine influences the course of HF [ 65 – 67 ]. Ivabradine in critically ill patients Critical care patients are prone to develop stress-induced car- diac impairment and consequently an increase in sympath tic tone. This, in turn, increases HR. In this setting, however, HR lowering might be difficult because the effects of inotropic drugs could be hindered by HR-reducing drugs like beta- 522 Heart Fail Rev (2018) 23:517 – 525