Guidelines for the Management of Patients with Heart Failure G. S

G. S

, G. S

, S. R

, A. P

, M. Z

, L. S

, F. L

, A. D

L

Chronic congestive heart failure (HF) is a highly disabling, costly, and deadly syndrome which affects a hundred million people worldwide [1]. Large clinical trials have shown that drugs which antagonise the renin–angiotensin–aldos- terone system [angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), aldosterone receptor antagonists] and sympa- thetic nervous system (beta-blockers) are highly effective in reducing the rates of mortality and morbidity in patients with left ventricular (LV) cham- ber dilation/systolic dysfunction cardiomyopathies, whether of ischaemic or non-ischaemic aetiology (Tables 1–3) [2–5]. Although no survival benefit has been documented with diuretics and digoxin, the former remain a corner- stone in the treatment of HF patients as the most efficacious means of coun- teracting fluid retention [6], while the latter can be of value to achieve fur- ther improvements in symptoms and quality of life [7].

In addition, several randomised controlled trials have recently demon- strated the effectiveness of implantable cardioverter defibrillator (ICD) ther- apy for the primary and secondary prevention of unexpected cardiac sudden death (Table 4) [8–10].

Despite the availability of these useful therapies, HF patients continue to be affected by progressively worsening symptoms, the need for recurrent high-cost hospitalisations, poor quality of life, and shortened life expectancy [11]. It is indisputable that the persistence of high morbidity and mortality rates can be explained, at least in part, by the fact that treatments proven to be effective in randomised controlled trials have not been applied to all suit- able patients encountered in the clinical arena [12]. Following from this, guidelines for the management of the syndrome have emerged in the last years as an helpful tool to translate scientific evidence into daily practice, providing indications for a more appropriate use of currently available ther- apeutic strategies [13, 14].

Department of Cardiology, Trieste Hospital and University, Trieste, Italy

Table 1.Randomised controlled trials with ACE inhibitors in HF Trial drugPatientsHF aetiologyNYHA (I–IV)LVEF Mean HF-related All-causeHF-relatedSudden testedfollow-uphospitalisationsmortalitymortalitymortality (n)(%)(months)(RR,%)(RR,%)(RR,%)(RR,%) CONSENSUS253MixedIVNA6NV앗27앗50– EnalaprilP= 0.003P< 0.001P= NS SOLVD-T 2569MixedII–III≤3541앗26앗16앗22앗10 EnalaprilP< 0.0001P= 0.0036P= 0.0045P= NS SOLVD-P4228MixedI–II≤3537앗44앗8앗21앗7 EnalaprilP< 0.001P= NSP= NSP= NS SAVE 2231Ischaemica I≤4042앗22앗19앗36– CaptoprilP= 0.019P= 0.019P= 0.032P= NS AIRE 2006Ischaemica II-IIINA15NE앗27NENE RamiprilP= 0.002 TRACE 1749Ischaemica I–IV≤3524NE앗22앗25앗24 TrandolaprilP= 0.001P= NSP= 0.03 ACE,angiotensin converting enzyme;HF,heart failure;LVEF,left ventricular ejection fraction;NA,not available;NE,not evaluated;NS,not sig- nificant;NYHA,New York Heart Association functional class;RR,relative risk;앗,reduced;—,unchanged;a Recent acute myocardial infarction

Table 2.Randomised controlled trials with ARBs and aldosterone receptor blockers in HF Trial drugPatientsHF aetiologyNYHA (I–IV)LVEF Mean HF-related All-causeHF-relatedSudden testedfollow-uphospitalisationsmortalitymortalitymortality (n)(%)(months)(RR,%)(RR,%)(RR,%)(RR,%) ELITE-II3152MixedII–IV≤4018NE_NE– LosartanaP= NSP= NS VAL-HeFT5010MixedII5010MixedII–IV≤4023앗27 ValsartanP= 2 CHARM7601MixedII–IV≤4038앗23앗13c앗앗 CandesartanP< 0.0001P= 0.006P< 0.00001P< 0.00001 RALES1663MixedIIIb–IV≤3524앗35앗30앗36앗29 SpironolactoneP< 0.001P< 0.001P< 0.001P< 0.02 EPHESUS6632IschaemicbI–IV앗or —16NE앗15NE앗21 EplerenoneP= 0.008P= 0.03 ARBs,angiotensin receptor blockers;HF,heart failure;LVEF,left ventricular ejection fraction;NE,not evaluated;NS,not significant;NYHA, New York Heart Association functional class;RR,relative risk;앗,reduced;— ,unchanged;aVersus captopril;bRecent acute myocardial infarc- tion;cFor cardiovascular reasons

Table 3.Large randomised controlled trials with beta-blockers in HF Trial drugPatientsHF aetiologyNYHA (I–IV)LVEF Mean HF-related All-causeHF-relatedSudden testedfollow-uphospitalisationsmortalitymortalitymortality (n)(%)(months)(RR,%)(RR,%)(RR,%)(RR,%) US TRIAL1094MixedII–III≤356앗27c앗65앗앗 CarvedilolP= 0.036P< 0.001P= NAP= NA ANZ TRIAL415IschaemicI–III≤4519앗23앗24–– CarvedilolP= 0.05P= NSP= NSP= NS CIBIS-II2647MixedIII≤3516앗20앗34앗26앗44 BisoprololP= 0.0006P < 0.0001P= NSP < 0.0001 MERIT-HF3991MixedII–III≤4012NV앗35앗49앗41 MetoprololP < 0.0001P < 0.0023P < 0.0002 COPERNICUS2289MixedIII–IV< 2521앗24d앗35NVNV CarvedilolP < 0.001P < 0.00014 CAPRICORN1959IschaemicbI–II ≤4016앗14e앗23앗40앗26 CarvedilolP= NSP= 0.031P= NSP= NS COMET3029MixedII–IV ≤3558앗3e앗17앗17앗19 CarvedilolaP= NSP= 0.0017P= NSP= 0.021 HF,heart failure;LVEF,left ventricular ejection fraction;NA,not available;NS,not significant;NYHA,New York Heart Association functional class;RR,relative risk;앗,reduced;— ,unchanged;aVersus metoprolol;bRecent acute myocardial infarction;cFor cardiovascular reasons;dFor HF;ePlus all-cause deaths

Table 4.Main primary and secondary prevention trials with ICD in asymptomatic/symptomatic left ventricular dysfunction TrialPatientsIHDNYHAMILVEFArrhythmia profileRCAControl therapyMean follow-upAll-cause mortalitySudden mortality (PP or SP)(n)(%)_________(months)(HR, 95% CI)(HR, 95% CI) MADIT (PP)196100II–III (~65%)10026 ± 7ns-VT, ind-VT0Various anti-arrhythmic drugs270.41 (0.24–0.69)0.25 (0.07–0.83) MUSTT (PP)704100I–II (~75%)9530 (< 40)ns-VT, ind-VT0Placebo390.49 (0.35–0.67)0.29 (0.16–0.52) MADIT II (PP)1232100I–II (~70%)10023 ± 6No arrhythmias0Placebo200.71 (0.56–0.92)0.39 (0.24–0.61) DEFINITE (PP)4580I–II (~70%)021 (7–35)ns-VT, frequent PVC0Placebo290.65 (0.40–1.06)b0.20 (0.06–0.71) COMPANION (PP)a152055III (~85%)NA21 (< 35)QRS > 120 ms 0CRT alone, placebo160.80 (0.68–0.95)c-dNA SCD-HeFT (PP)252151II–III (100%)NA25 (20–30)No arrhythmias0Amiodarone, placebo480.77 (0.62–0.96)dNA AVID (SP)101682I–II (~90%)6732 ± 13VF, s-VT45Amiodarone, sotalol180.66 (0.51–0.85)0.44 (0.28–0.70) CASH (SP)28873I–II (~80%)5145 ± 17VF, s-VT100Amiodarone, metoprolol, propafenone570.82 (0.60–1.11)0.39 (0.22–0.67) CIDS (SP)65983I–II (~90%)7734 ± 14VF, s-VT, ind-VT48Amiodarone350.85 (0.67–1.10)0.70 (0.45–1.09) HF,heart failure;IHD,ischaemic heart disease;ind-VT,inducible sustained ventricular tachycardia;LVEF,mean left ventricular ejection fraction;MI, previous myocardial infarction;NA,not available;ns-VT,nonsustained ventricular tachycardia;NYHA,New York Heart Association functional class; HR,hazard ratio;PP,primary prevention ofsudden death;PVC,premature ventricular complexes;RCA,resuscitated cardiac arrest;SP,secondary prevention ofsudden death;s-VT,sustained ventricular tachycardia;VF,ventricular fibrillation;aImplantable cardioverter defibrillator plus cardiac resynchronisation therapy;bStatistically not significant;cPlus all-cause hospitalisation ;dVersus placebo

Conventional Pharmacological Therapies

All patients who are symptom-free [New York Heart Association (NYHA) class I] and have impaired LV pump function (ejection fraction, EF <

40–45%) should receive an ACE inhibitor; the addition of a beta-blocker can be recommended only in those who have asymptomatic LV systolic dysfunc- tion following an acute myocardial infarction.

The established treatment for HF patients with NYHA class II–IV symp- toms and reduced LVEF comprises an ACE inhibitor (or, if not tolerated, an ARB), a beta-blocker, one or more diuretics (including an aldosterone recep- tor antagonist), and possibly digoxin. The first step is to introduce an ACE inhibitor, which can be initiated before diuretic therapy in patients who show a low tendency to develop fluid retention; however, most patients exhibit congestive signs/symptoms, and thus these two forms of treatment are usually initiated at the same time. ACE inhibitor drugs must be started at low doses and slowly titrated up to those proven to be effective in the clinical trials (or, alternatively, to the maximum tolerated). ACE inhibitor treatment should not be initiated (or, if already started, it must be stopped) in patients with evidence of bilateral renal artery stenosis, angio-oedema, intractable dry cough, hypotension (systolic blood pressure < 80 mmHg), severe renal impairment (creatininaemia > 3.0 mg%) or electrolyte abnormalities (kalaemia > 5.5 mmol/l).

Some mildly symptomatic cases can be managed with a thiazide diuretic, but most patients require to be treated with a loop diuretic, perhaps given at high doses or in combination with metolazone in the presence of severe con- gestive signs/symptoms. During chronic diuretic therapy, it is necessary to check serum creatinine, electrolytes, uric acid, and glucose frequently.

In clinically stable patients on optimised treatment with an ACE inhibitor and diuretics, addition of a beta-blocker is indicated (only bisoprolol, long- acting metoprolol, and carvedilol can be recommended at present), unless they are intolerant or have any contraindication to this form of treatment (contraindications include bronchial asthma, severe bronchial disease, symp- tomatic bradycardia, advanced heart block, and symptomatic hypotension).

Patients who undergo beta-blocker therapy should be closely followed dur-

ing the up-titration phase and thereafter in order to ensure prompt recogni-

tion of the occurrence of major side effects (bradycardia, hypotension, fluid

retention, worsening HF). Initial doses must be very low and must be

increased slowly up to the optimal ones. If side effects occur, all attempts

should be made to avoid discontinuation of the beta-blocker, by changing

the ACE inhibitor and/or diuretic doses. If there is a need to reduce or stop

the beta-blocker therapy, every effort should be made to reintroduce it when

the patients become clinically stable.

Although ARBs have not been shown to be superior to ACE inhibitors, they are also effective on major clinical end points. Thus, if ACE inhibitors are contraindicated or not tolerated, ARBs represent the best alternative choice. Moreover, in patients receiving an ACE inhibitor and a beta-blocker, the addition of an ARB may provide further clinical benefits. Side effects are less frequent with ARBs than with ACE inhibitors.

The addition of spironolactone or eplerenone to an ACE inhibitor, a beta blocker, and possibly diuretics and digoxin is recommended in patients with severe HF and in those with symptomatic LV systolic dysfunction following an acute myocardial infarction. Renal function and serum electrolytes must be checked periodically. The administration of an aldosterone receptor antagonist should be avoided or stopped in patients with creatininaemia >

2.5 mg/dl, kalaemia > 5.0 mmol/l, or painful gynaecomastia.

Digoxin is indicated in HF in order to slow the ventricular rate when atri- al fibrillation is present or to improve clinical status when symptoms persist despite optimal ACE inhibition and diuretic therapy; there is no clear evi- dence that the drug may be of value in patients on sinus rhythm receiving an ACE inhibitor, a beta-blocker, and diuretics. Digoxin therapy is contraindi- cated in the presence of bradycardia, advanced heart block, sick sinus syn- drome, carot id sinus sy ndrome, Wolff-Parkinson-White sy ndrome, hypokalaemia, or hypercalcaemia. Serum creatinine and potassium should be assessed before initiating the treatment.

Adjunctive Pharmacological Therapies

Given the disappointing results that have emerged from large randomised controlled trials on pure vasodilating, positive inotropic, and anti-arrhyth- mic agents, there is no firm recommendation to use such classes of drug for the treatment of HF. However, nitrates remain an essential pharmacological tool to manage patients with concomitant angina or acute dyspnoea, and felodipine and amlodipine represent an additional option for patients with active ischaemic cardiomyopathy or arterial hypertension. Intravenous inotropic support may be unavoidable to counteract severe episodes of wors- ening HF or as a bridge to heart transplant in end-stage HF. The use of amio- darone may be indicated in association with a beta-blocker to treat some patients with atrial fibrillation/flutter or with non-sustained/sustained ven- tricular tachycardia.

In HF patients with prior myocardial infarction, either aspirin or oral

anticoagulants are recommended as secondary prevention. Anticoagulation

therapy is also firmly indicated in HF patients with atrial fibrillation, a histo-

ry of previous thromboembolic events, or evidence of a mobile LV thrombus.

Nonpharmacological Therapies

The prevention of sudden death in patients with HF continues to represent a hard challenge since medical treatments have had only a limited impact on this mode of death. Recent clinical trials have shown that ICD therapy reduces the rate of mortality among patients resuscitated from a cardiac arrest or with a history of sustained ventricular tachycardia poorly tolerated and/or associated with low LVEF. There is also evidence that the use of ICD as the primary prevention strategy improves the survival rate of patients with NYHA class II–III symptoms and LVEF below 35%. Moreover, when associated with biventricular pacing to treat ventricular dyssynchrony (QRS width > 120 ms), the ICD has been shown to reduce all-cause deaths and/or hospitalisations in patients with LVEF below 35% and NYHA class III–IV symptoms. All these benefits observed with the ICD therapy are additive to optimal pharmacological treatment, regardless of the aetiology of the car- diac disease.

Given the high costs and the subsequent low availability of these devices, it is necessary to define better their short-term and long-term cost-effective- ness and also to refine the selection of patients who are likely to benefit most from an ICD.

Treatment of Diastolic Heart Failure

There is little evidence from randomised controlled trials to support firm recommendations for the treatment of patients with HF due to exclusive or prevalent LV diastolic dysfunction.

ACE inhibitors, ARBs, beta-blockers, and verapamil-type calcium antago- nists are useful to treat underlying conditions (myocardial ischaemia, arteri- al hypertension) and have the ability to improve LV diastolic properties through a number of different mechanisms; thus, there is the potential for beneficial effects from the use of these drugs.

Digoxin may be indicated in patients with concomitant atrial fibrillation,

alone or in combination with a beta-blocker or verapamil. The administra-

tion of diuretics and nitrates may be necessary when episodes of fluid over-

load or acute dyspnoea occur, but they should be given cautiously in order to

avoid an excessive preload reduction, which in turn might lead to a critical

fall in cardiac output.

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