Best of heart failure

42 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 activity, 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 angioed ma [ 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 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, 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 qu stionnaire scor s increased significantly ( p = 0.003) after the ivabradine treatment; on the contrary, significant decrease in HR was revealed as expected. Th se initial results seem promising that ivabradine has favorable effects on ED. These findings were postulated to be depende t exclusively on HR reduction [ 55 ]. Ivabradine in heart failure with preserved ejection raction HF with preserved ejectio fraction (HFpEF) accounts for up to 50% of all incid nt cases of HF, nd its prevalence is rising as a result of the aging population [ 56 ]. An elevated HR is a predictive factor of worse outcomes and increased mortality in patients with HF, including HFpEF [ 56 ]. In HFpEF animal models, ivabradine was shown to reduce cardiac fibrosis and improve vascular stiffness and LV systolic and diastolic func- tion [ 56 , 57 ]. Patients with LV diast lic dysfunction are char- acterized by exertional dyspnea. HR reductio by beta- blockers can improv exercise tolerance by rolonging LV filling, but th ir negative inotropic and lusitropic propertie can be detrimental in this disease. In the pilot study of Fischer-Rasokat t al., 24 patients with CAD and normal LVEF on chronic beta-blocker th rapy were included. Beta- bl ckers w r replaced b ivabradine and pati nts were re- tested after 6 weeks [ 58 ]. E/e ’ significantly decreased du ing ivabradine ther py in patients with high E/e ’ (10.7 ± 2.9 vs 8.9 ± 1.7; p < 0.01), whereas no difference occurred in patients with low E/e ’ (6.4 ± 0.7 vs 6.5 ± 1.1; p = ns). With ivabradine, pat ents with high E/e ’ had an increased oxygen uptake at the ana robic threshold (from 10.8 ± 1.4 to 11.8 ± 1.9 mL/min/kg; p < 0.05) and a steep r slope of the initi l oxygen pulse curve (from 293 ± 109 to 359 ± 117 μ L/b at/kg/W; p < 0.05). Moreover, patients with high E/e ’ had lower N-terminal pro- brain natriuretic peptide (NT-proBNP) serum levels at rest (169 ± 207 vs 126 ± 146 pg/mL; p < 0.05) and after exercise (190 ± 256 vs 136 ± 162 pg/mL, p < 0.05) during ivabradine therapy [ 58 ]. The sults of this study sugg st that vabradine may be a suitable alternative in patients with CAD and a greater than nor al LV filling index who do n t tolerate be ta-blockade. Moreover, switching therapy from beta-blockers Table 1 Clinical trials investigating ivabradine in patients with left ventricular systolic dysfunction Study Design Efficacy outcomes BEAUTIFUL [ 20 ] Randomized, double-blind, place o-controll d, parallel-group trial; ivabradi e ( n = 5479) and placebo ( n = 5438); median follow-up — 19 months Ivabradine did not affect the primary endpoint (comp site of cardiovascular death, admission to hospital for acute myocardial infarction, and admission to hospital for new onset or worsening heart failure), but it did reduce seco dary endpoint : admission to hospital for fatal and non-fatal myocardial infarction (0.64, 95% CI 0.49 – 0.84, p = 0.001) and coronary revascularization (0.70, 95% CI 0.52 – 0.93, p = 0.016) CARVIVA HF [ 50 ] Randomized open-blinded endpoint study; carvedilol ( n = 38) versus ivabradine ( n = 47) versus carvedilol plus ivabr dine ( n = 42), follow-up — 3 m nths Improvement in 6-min walking test, the exercise time on mixed venous oxyge saturation test ( p < 0.01), peak oxygen uptake, and ventilatory anaerobic threshold ( p < 0.03) in th iv bradine a d com ination (ivabradine plus carvedilol) groups; better quality of life ( p < 0.01 vs baseline for ivabradine and p < 0.02 for combination) versus no change with carvedilol SHIFT [ 51 ] Double-blind placebo-controlled stud , n = 6558; plac bo group ( n = 3264) a d ivabradine group ( n = 3241); median follow-up — 22.9 months 24% patie ts in the ivabradine group and 29% in pl cebo group had a primary endpoint event (the composite of cardiovas ular death or hospital admission for worsening heart failure) (hazard ratio 0.82, 95% CI 0.75 – 0.90, p < 0.0001) The eff cts were driven mainly by hospital admi sions for worsening heart failure (672 [21%] placebo vs 514 [16%] ivabradine; hazard ratio 0.74, 0.66 – 0.83; p < 0.0001) and deaths due to heart failure (151 [5%] vs 113 [3%]; hazard ratio 0.74, 0.58 – 0.94, p = 0.014) INTENSIFY [ 52 ] Prospective, open-label multicenter study, follow- p — 4 month, ( n = 1956) Heart rate reduction to 67 ± 8.9 bpm; signs of decompensation decreased to 5.4%; patients with BNP levels > 400 pg/mL dropped to 26.7%, a shift in NYHA classification towards lower grading (24.0 and 60.5% in NYHA I and II, respectively); improvement of EQ5D to 0.79 ± 0.21 CI confidenc interval, BNP brain natriuretic peptide, NYHA New York Heart Association, EQ5D Eur Qol-5 Dimension Heart Fail Rev (2018) 23:517 – 525 521