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Sacubitril-valsartan should not be given concomitantly it ACE in ibitors due to risk for ngioedema, 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 sever 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 wi h 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 fo atients with chronic HFrEF to r duce 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 administer d concomitant y 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 a 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 ale t 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 val artan at 12 weeks and was well tolerated [ 39 ]. The efficacy 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 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 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 inte ded to recruit patients on target or maximally tolerat d 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 compone t 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 patie ts 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 pati nts 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, iv bradine 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 regard ng 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 w s not designed to exa in the efficacy of ivabr dine in patients intolerant to bet -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 re uced 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 Ultrafiltration The interdepen ence of cardiac and renal func- tion is well rec gnized, with dysfunction of one organ com- monly affecting the other. Balancing cardiac decongestion and renal f c ion is a common strugg e tha physic a s face when reating acute d compensated HF patients [ 58 ]. Ultrafiltration offers an option to further decongest HF patients with renal dysfunction. However, the current data on isk-b nefit analy- sis is inconclusive. The Cardio enal escue Study in Acut Decomp ns ted Heart Failure (CARRESS-HF) rial tested th effects of ult afiltration for continued fluid removal in the presence of worsening renal failure but demonstrated an in creas d ass ciation wit mor a verse vents, worsening renal function, and no signi icant difference in clinical outcomes [ 59 ]. Alternatively, the AVOID-HF (Aquapheresis Versus Intraven us Diuretics and Hospitalizations for Heart Fa lure) trial did not se a difference in adver e events betw en ultr - filtration and loop diuretic tr atment groups [ 60 ]. Importantly, there was a longer duration betw en initial a d subsequent HF events with n 90 days in the ultrafiltration group compared to diuretic the apy. This study w s er inated ear y for fundi g reasons but provides incentiv to urther evaluate its validity as part of an empiric strategy for congestion refractory to aggressive pharmacologic therapy [ 61 – 63 ]. Identify and treat noncardiac comorbidities Heart failure exacerbations commonly re ul from the interplay between the underlying cardiac substrate and amplifying mechanisms such as diabetes melli us, renal failure, and COPD. In patients with HF, a ignificant number experience rehospitalizations or death secondary to comorbidities rather than heart disease it elf. The progn st c sig ificance of noncar- diac comor idities is equally impo tant in HF patient with preserved, mid-range, and reduced ej c ion fraction [ 64 ]. In HFpEF, with p tential exception of spironolactone, random ized control d tri s of various therapies have thus far fail d to demonstrate improved outcomes. Therefore, there is an in- creased inter st in t rgeting and opt mizing comorbidit es as a t mporizing measure pending further research for proven ther- apies. The prevale ce and pr g os ic i plicatio s of comor- bidities in HFrEF and HFpEF have been previously discussed, but a few specific comorbidities deserv notable mention. Co orbid diabetes m llitus and heart di ease h ve been shown to hav si nificantly poor overall outcomes. Concu rent diabetes can be seen in up to 44% of HFrEF patients [ 65 ] and 32 – 45% of HFpEF patients [ 66 ]. Among patients with diabetes, the most common clinical complication is due to cardiovascular disease, especi lly HF [ 67 ]. However, cumulative data from pri- or studies suggests that hyp rglycemia per se is n t a therapeutic target i HF, with multiple glucose-lowering ther pies co ferring heightened risk for HF events despit add d glucose control [ 68 , 69 ]. In the recent EMPA-REG OUTCOME (Em agliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes) tudy, mpagliflozin, a sodium – glucose cotransporter-2 (SGLT2) inhibitor, demonstrated a positive effect on cardiovas- cular risk [ 70 ]. Specifically, there was a reduc io in m rtality secondary to cardiovascul etiology as well as a decreased risk of ospitalization for HF compared to placebo (haz rds ratio 0.65) [ 71 ]. Similar fin ings were seen with canagliflozin, another SGLT2 inhib t r, in t CANVAS (Canagliflozin Cardi vascular Asses ment Stu y) trial [ 72 ]. T e mechanism of im roved car- diac outco es is not th ugh to be due to glycemic control, but the xact pathophysio ogy is still un nown. Iron deficiency is a common comorbidity in chronic HF that has been s own to be an indicator of more advanced disease [ 73 ] as w ll as reduce functional c pacity and quality of life [ 74 ]. Iron deficiency itself has been seen in 33% of CHF patients with or withou anemia and is associated with a re- d ced ev nt-f e survi al at 36 months [ 75 ]. The defici ncy of iro p cifically is related to poo outcomes ndepend nt of anemia r bone marrow hypoproduction. The RED-HF (Reduction of Events with Darbep etin Alfa in Heart Failure) trial demonstrated no benefit with treatment with darbep etin injections i patients with iron-deficiency ane i [ 76 ]. The IRONOUT-HF (Iron Repletio Effects on Oxygen Up ake in Heart Failure) trial did ot de onstr te ben fit in r utine oral iron supplementati s in HFrEF patients with iron deficiency bas d on exercise tolerance (6MWT) and peak ox- ygen uptake [ 77 ]. However, studies have shown improved outcom s with intravenous (IV) iron supplem ntation. Th FAIR-HF (Ferinject Assessment in Patients with Iron Deficiency a d Chronic Heart Failure) study demonstrated improvement in pat ent-reported quality of life and x rc se capacity with intravenous ferric c rboxymaltose (FCM) in ir n-d ficient patients with nd without anemia [ 78 ]. The trial also found a significan ly lower rate of death due to wo sening HF in the FCM arm. Likewise, the CONFIRM-HF (Ferric C rboxymaltose Evaluation o P rform nce in Pa ients with Ir n Defici cy in Combination with Chronic Heart Failure) trial demonstrated similar results with an improvement in functi nal capacity measu e with 6MWT [ 79 ]. In the EFFECT-HF (Effect of Ferri Carboxymaltose on Exercis Cap ity in P tie ts w th Heart Failure a d Iron Deficiency) trial, the treatm t with IV FCM also improved peak xygen consumption, an obj ctive marker of exercise tolerance [ 80 ]. Emphasize post-discharge follow-up visits There is a period about 2 – 3 mo ths after discharge known as the vulner ble phase when morbidity and mortality signifi- cantly incr ase comp r d to any other point in the timeline from admission [ 81 ]. This is usually due to short-term wors- ening of hemodynamics in the setting of suboptimal therap , medicati n and diet noncompliance, and other fact rs. It is Heart Fail Rev (2018) 23:597 – 607 603

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