Goals of treatment of chronic CHF are to:
General principles of therapy
In newly diagnosed patients with CHF, congestion and volume overload should be promptly treated with diuretics, which may be given intravenously in the initial phase. Loop diuretics used for the treatment of heart failure and congestion include furosemide, bumetanide, and torasemide.
In patients with low left ventricular ejection fraction (LVEF), in addition to diuretics, ACE inhibitors, beta-blockers, and aldosterone antagonists (e.g., spironolactone, eplerenone) should be added.
In unstable patients, beta-blockers should be initiated only after stabilisation, optimisation of volume status, and discontinuation of inotropes. Beta-blockers should be initiated at a low dose.
In patients with CHF and reduced LVEF who are hospitalised with exacerbation of heart failure, unless there is evidence of low cardiac output or haemodynamic instability or contraindication, both ACE-inhibitors and beta-blockers should be continued.
The success of pharmacological therapy is strongly related to, and greatly enhanced by, encouraging the patient and his/her family to participate in various complementary non-pharmacological management strategies. These mainly include lifestyle changes, dietary and nutritional modifications, exercise training, and health maintenance.
Initial drug treatments
All patients with symptoms and signs of congestion should receive diuretics, irrespective of the LVEF. In patients with reduced LVEF, diuretics should always be used in combination with an ACE inhibitor (or angiotensin-II receptor antagonist), a beta-blocker, and an aldosterone antagonist. Loop diuretics used for the treatment of heart failure and congestion include furosemide, bumetanide, and torasemide. The most commonly used agent appears to be furosemide, but some patients may respond more favourably to another loop diuretic. In resistant cases, loop diuretics should be combined with a thiazide diuretic (e.g., chlorothiazide, hydrochlorothiazide) or a thiazide-like diuretic (e.g., metolazone, indapamide).
Loop diuretics and thiazide diuretics differ in their pharmacological actions. Loop diuretics increase excretion of up to 20% to 25% of the filtered load of sodium, enhance free-water clearance, and maintain their efficacy unless renal function is severely impaired. In contrast, thiazide diuretics increase the fractional excretion of sodium to only 5% to 10% of the filtered load, tend to decrease free-water clearance, and lose their effectiveness in patients with impaired renal function (i.e., creatinine clearance less than 40 mL/minute). Consequently, loop diuretics have emerged as the preferred diuretic agents for use in most patients with heart failure; however, thiazide diuretics may be preferred in patients with hypertension, heart failure, and mild fluid retention because they confer more persistent antihypertensive effects.
Careful monitoring of renal function and electrolytes is essential. The minimum dose of diuretic should be used to relieve congestion, keep the patient asymptomatic, and maintain a dry weight.
ACE inhibitors or beta-blockers:
ACE inhibitors or beta-blockers may be used as first-line treatment. Both are equally important in terms of survival benefit. It has not been shown that starting with an ACE inhibitor is better than starting with a beta-blocker, but in practice most physicians start an ACE inhibitor first; the origin of this practice is historical, as the benefits of ACE inhibitors were demonstrated 10 years before those of beta-blockers. Also, most large-scale studies of beta-blockers were conducted using ACE-inhibitor therapy as comparator or standard. If a patient cannot tolerate target doses of both an ACE inhibitor and a beta-blocker when these drugs are co-administered, it is preferable to co-administer lower doses of both drugs than to reach the target dose in one class and not be able to initiate the other.
ACE inhibitors have been shown to decrease the morbidity and mortality associated with heart failure, and should be given to all patients with left venticular (LV) dysfunction, symptomatic or otherwise, unless there is a contraindication or prior intolerance to therapy.
Beta-blockers have also been shown to decrease the morbidity and mortality associated with heart failure. They are initiated at low doses and titrated to target dosage. One meta-analysis found that irrespective of pre-treatment heart rate, beta-blockers reduced mortality in patients with heart failure with reduced ejection fraction (HFrEF) in sinus rhythm. Achieving a lower heart rate is associated with better prognosis for patients in sinus rhythm but not those with atrial fibrillation. Mortality was lower for patients in sinus rhythm randomised to beta-blockers (hazard ratio: 0.73 vs. placebo; 95% confidence interval [CI] 0.67 to 0.79; P <0.001), regardless of baseline heart rate (interaction P = 0.35). Beta-blockers had no effect on mortality in patients with atrial fibrillation (hazard ratio: 0.96; 95% CI 0.81 to 1.12; P = 0.58) at any heart rate (interaction P = 0.48). However, this was a retrospective analysis and authors commented that background therapy, including devices, may have changed since these trials were conducted and that the heart rate was not measured in a standardised fashion across the trials. In a randomised trial of patients with atrial fibrillation and HFrEF, during a median follow-up of 37 months, beta-blockers were associated with significantly lower all-cause mortality (hazard ratio: 0.721; 95% CI 0.549 to 0.945; P = 0.0180) but not hospitalisation (hazard ratio: 0.886; 95% CI 0.715 to 1.100; P = 0.2232). The result of this study supports the evidence-based recommendations for beta-blockers in patients with HFrEF, whether or not they have associated atrial fibrillation.
Although side effects can include bradycardia, worsening of reactive airway disease, and worsening heart failure, these can often be avoided by careful patient selection, dose titration, [ ] and close monitoring. Clinical improvement may be delayed and may take 2 to 3 months to become apparent. However, long-term treatment with beta-blockers can lessen the symptoms of heart failure and improve clinical status.
Angiotensin-II receptor antagonists:
Angiotensin-II receptor antagonists are considered a reasonable alternative to ACE inhibitors in patients with preserved or decreased LVEF who are intolerant of ACE inhibitors because of cough or angio-oedema. Experience with these drugs in controlled clinical trials of patients with heart failure is considerably less than that with ACE inhibitors. Nevertheless, valsartan and candesartan have demonstrated benefit by reducing hospitalisations and mortality. In patients with evidence of left ventricular dysfunction early after myocardial infarction, angiotensin-II receptor antagonists may be no more effective than ACE inhibitors and may be no better tolerated. The combination of an ACE inhibitor and an angiotensin-II receptor antagonist may produce more reduction of left ventricular size and may reduce the need for hospitalisation than either agent alone, although whether or not combination therapy further reduces mortality remains unclear. As an alternative to ACE inhibitors, angiotensin-II receptor antagonists should be initiated in patients early post-infarct, but caution should be used in patients in cardiogenic shock or with marginal renal output.
Addition of an angiotensin-II receptor antagonist may be considered in persistently symptomatic patients with heart failure and reduced LVEF who are already being treated with an ACE inhibitor and beta-blockers and in whom an aldosterone antagonist is not indicated or tolerated. Routine combined use of ACE inhibitors with an aldosterone antagonist and an angiotensin-II receptor antagonist is potentially harmful for patients with heart failure and is not recommended. Combined use should be instigated by a specialist and continued only with specialist supervision. Concomitant administration of an ACE inhibitor, a beta-blocker, and an angiotensin-II receptor antagonist should be used with great caution and perhaps initiated only in hospital under continuous blood pressure and renal function monitoring, because it may provoke life-threatening hypotension and acute renal insufficiency. The CHARM trial showed that this combination may confer added benefit with acceptable risk, but further studies are required. In one study, addition of olmesartan (an angiotensin-II receptor antagonist) to patients with New York Heart Association (NYHA) class II to IV heart failure who had a history of hypertension or who had been treated with antihypertensive medications and were already on ACE inhibitor and beta-blocker therapy did not improve the clinical outcome and led to worsening of renal function. In this study, subgroup analysis showed that the addition of olmesartan to a combination of an ACE inhibitor and a beta-blocker was associated with an increased incidence of primary end point, all-cause death, and renal dysfunction. The routine combined use of all three inhibitors of the renin-angiotensin system cannot be recommended at present. The European Medicines Agency's Pharmacovigilance Risk Assessment Committee has advised that combining drugs that act on the renin-angiotensin system (e.g., ACE inhibitors, angiotensin-II receptor antagonists) is not recommended, particularly in patients with diabetes-related kidney problems. Where such a combination is considered absolutely necessary, it should be carried out under strict specialist supervision with close monitoring.
Renin inhibitors (e.g., aliskiren) should also not be combined with ACE inhibitors. In a study of patients with chronic heart failure (NYHA class II to IV, ejection fraction of 35% or less) addition of aliskiren to enalapril compared with enalapril alone led to more adverse events (hypotension and elevated creatinine) without any benefit or difference in primary outcome of death from cardiovascular causes or hospitalisation for heart failure.
Angiotensin-II receptor antagonist plus neprilysin inhibitor:
In HFrEF (NYHA class II to IV) and ejection fraction of 40% or less, which was later changed to an ejection fraction of 35% or less, a combination of sacubitril, a neprilysin inhibitor, and valsartan, an angiotensin-II receptor antagonist, was superior to enalapril in reducing mortality and heart failure hospitalisation. The drug combination has been approved in the US and in Europe for the treatment of heart failure. In this study the ejection fraction was 29 ± 6.1% in the sacubitril/valsartan group and 29.4 ± 6.3% in the enalapril group.
Sacubitril/valsartan has been found to improve a patient's physical and social activities compared with enalapril.
Sacubitril/valsartan is recommended as a replacement for an ACE inhibitor in patients who remain symptomatic despite optimal treatment with an ACE inhibitor, a beta-blocker, and a mineralocorticoid-receptor antagonist. It is recommended for patients who fit the profile of the study showing beneficial effects of this combination (i.e., patients in NYHA class II to IV with LVEF of 35% or <35%). The American Heart Association/American College of Cardiology/Heart Failure Society of America guidelines recommend that, in patients with chronic NYHA class II or III who tolerate an ACE inhibitor or angiotensin-II receptor antagonist, these drugs should be replaced by an angiotensin-II receptor antagonist plus neprilysin inhibitor to further reduce morbidity and mortality. Concomitant administration of an angiotensin-II receptor antagonist plus a neprilysin inhibitor with an ACE inhibitor, or within 36 hours of the last dose of an ACE inhibitor, is not recommended.
Treatment with sacubitril/valsartan reduces cardiovascular death by reducing both worsening heart failure and sudden cardiac death.
Hydralazine and nitrates:
The addition of a combination of hydralazine and a nitrate is reasonable for patients with reduced LVEF who are already taking an ACE inhibitor and beta-blocker for symptomatic heart failure and who have persistent symptoms, and has demonstrated benefit in black patients with heart failure. The combined use of hydralazine and isosorbide dinitrate may also be considered as a therapeutic option in patients who are intolerant of ACE inhibitors. This combination may be a useful alternative in patients intolerant to both ACE inhibitors and angiotensin-II receptor antagonists.
A combination of hydralazine and isosorbide dinitrate can be useful to reduce morbidity or mortality in patients with current or prior symptomatic HFrEF who cannot be given an ACE inhibitor or angiotensin-II receptor antagonist because of drug intolerance, hypotension, or renal insufficiency, unless contraindicated. The American College of Cardiology Foundation/American Heart Association guidelines recommend the combination of hydralazine and isosorbide dinitrate to "reduce morbidity and mortality in patients self-described as African Americans with NYHA class III to IV HFrEF receiving optimal therapy with ACE inhibitors and beta blockers, unless contraindicated".
At present there is little evidence from long-term studies to recommend antiplatelet therapy or oral anticoagulation in patients with heart failure in sinus rhythm, and antiplatelet agents versus control or anticoagulation for heart failure in sinus rhythm. [ ]
A study comparing warfarin and aspirin in patients with heart failure and sinus rhythm showed no significant difference in the combined outcomes of stroke, intracerebral haemorrhage, and death. Warfarin reduced ischaemic stroke at the expense of an increased bleeding risk. [ ]
Although oral anticoagulants are indicated in certain groups of patients with heart failure (e.g., patients with atrial fibrillation), the available data do not support their routine use in heart failure patients who remain in sinus rhythm.
Digoxin for patients with heart failure
Digoxin can be beneficial in patients with current or prior symptoms of heart failure or reduced LVEF, especially those with atrial fibrillation. When added to ACE inhibitors, beta-blockers, and diuretics, digoxin can reduce symptoms, prevent hospitalisation, control rhythm, and enhance exercise tolerance. Digoxin reduces the composite end point of mortality or hospitalisations in ambulatory patients with chronic heart failure with NYHA class III or IV symptoms, LVEF <25%, or cardiothoracic ratio of >55% and should be considered in these patients.
Digoxin reduces the composite end point of mortality or hospitalisations, but does not reduce all-cause mortality. Digoxin should be used cautiously with plasma level monitoring. One meta-analysis suggests that digoxin use in patients with heart failure is associated with a higher risk of all-cause mortality.
One systematic review and meta-analysis of observational and controlled trial data showed that digoxin has a neutral effect on mortality in randomised trials and reduces hospital admissions.
Aldosterone antagonists in moderate-to-severe heart failure
Aldosterone antagonists (also known as mineralocorticoid receptor antagonists) decrease the morbidity and mortality associated with symptomatic chronic heart failure.
Aldosterone antagonists (spironolactone and eplerenone) are recommended in patients with NYHA class II to IV heart failure who have LVEF of 35% or less, unless contraindicated. They are also recommended to reduce mortality and morbidity following acute myocardial infarction in patients with LVEF of 40% or less who develop symptoms of heart failure or have a history of diabetes mellitus, unless contraindicated.
Aldosterone antagonists should be initiated after titration of standard medical therapy. Spironolactone and eplerenone can both cause hyperkalaemia, and precautions should be taken to minimise the risk. In the EPHESUS trial, the addition of eplerenone to standard care did not increase the risk of hyperkalaemia when potassium was regularly monitored.
Ivabradine is approved for use in patients with heart failure and symptoms in spite of drug therapy. The UK National Institute for Health and Care Excellence has approved it for patients with NYHA class II to IV heart failure, sinus rate of over 75 bpm, and ejection fraction <35%. In the US, the Food and Drug Administration (FDA) has approved it to reduce the risk of hospitalisation for worsening heart failure in patients with stable, symptomatic chronic heart failure, with LVEF ≤35%, who are in sinus rhythm with a resting heart rate ≥70 beats per minute, and are either on a maximum dose of beta-blockers or have a contraindication to beta-blockers.
In a randomised, double-blind, placebo-controlled trial, addition of ivabradine to standard background therapy in patients with stable coronary artery disease without clinical heart failure (no evidence of left ventricular systolic dysfunction in the overall study population, mean ejection fraction was 56.4%) did not improve the outcome. In the subgroup analysis of this study, ivabradine was associated with an increase in the incidence of the primary end point (death from cardiovascular causes or non-fatal myocardial infarction) among patients who had angina of Canadian Cardiovascular Society class II or higher but not among patients without angina or those who had angina of class I. Ivabradine was associated with an increased incidence of bradycardia, QT prolongation, and atrial fibrillation.
Use of vasopressin antagonists such as tolvaptan can be considered for patients with symptomatic or severe hyponatraemia (<130 mmol/L) and persistent congestion despite standard therapy, to correct hyponatraemia and related symptoms.
Heart transplant and medical devices
Cardiac transplantation is currently the only established surgical approach, but it is available to fewer than 2500 patients in the US each year. Current indications for cardiac transplantation focus on the identification of patients with severe functional impairment, dependence on intravenous inotropic agents, recurrent life-threatening ventricular arrhythmias, or angina that is refractory to all currently available treatments.
Implantable defibrillators have been shown to decrease mortality in patients with heart failure, both ischaemic and non-ischaemic. The SCD-Heft trial enrolled patients who had left ventricular dysfunction and no prior history of syncope or sustained ventricular tachycardia, and included patients with a prior myocardial infarction and no prior coronary artery disease. Use of implantable defibrillators led to a 23% relative mortality risk reduction at 5 years.
It has been estimated that one quarter to one third of patients with heart failure have left bundle-branch block: that is, manifest a QRS duration greater than 120 milliseconds (ms). Patients with heart failure who have left bundle-branch block, known as ventricular dyssynchrony, have a poorer prognosis than those without left bundle-branch block. Studies have shown that, in these patients, cardiac re-synchronisation therapy (CRT) decreases hospitalisation and, when combined with an implantable defibrillator, significantly reduces mortality. In patients who have conduction delay and left ventricular dysfunction, biventricular pacemakers have been shown to improve exercise tolerance and quality of life while decreasing morbidity and mortality. The CARE-HF study randomised patients with a widened QRS, LVEF of 35% or less, and persistent moderate or severe symptoms of heart failure despite pharmacological therapy, to implantation of a CRT device or not. The main study observed substantial benefits on morbidity and mortality that persisted or increased with longer follow-up. Reduction in mortality was due to fewer deaths from heart failure and from reduced sudden death.
The FDA approved the use of CRT devices for patients in NYHA class II heart failure, an LVEF <30%, left bundle-branch block, and QRS width >130 ms. Long-term data from the REVERSE study suggest that improvements in left ventricular function and remodelling can be sustained for over 5 years.
According to the American College of Cardiology Foundation/American Heart Association guidelines, the recommendations for the use of CRT devices in heart failure are as follows.
CRT is indicated in patients who have LVEF of 35% or less; sinus rhythm; left bundle-branch block (LBBB) with a QRS duration of 150 ms or greater; NYHA class II, III, or ambulatory IV symptoms on guideline-directed medical therapy.
CRT can be useful in patients who have LVEF of 35% or less; sinus rhythm; a non-LBBB with a QRS duration of 150 ms or greater; NYHA class III/ambulatory IV symptoms on guideline-directed medical therapy.
CRT can be useful in patients who have LVEF of 35% or less; sinus rhythm; LBBB with a QRS duration of 120 to 149 ms; NYHA class II, III, or ambulatory IV symptoms on guideline-directed medical therapy.
CRT can be useful in patients with atrial fibrillation and LVEF of 35% or less on guideline-directed medical therapy if (a) the patient requires pacing or otherwise meets the CRT criteria; and (b) atrioventricular nodal ablation or pharmacological rate control will allow near 100% ventricular pacing with CRT.
CRT can be useful for patients on guideline-directed medical therapy who have LVEF of 35% or less and are undergoing device implantation with anticipated requirement for significant (>40%) ventricular pacing.
American Heart Association guidance outlines the indication and evidence behind the use of mechanical circulatory support in patients with heart failure. Mechanical circulatory support, which includes ventricular assist devices, is beneficial in carefully selected patients with end-stage D heart failure in whom definite management ( e.g., cardiac transplantation) or cardiac recovery is anticipated.
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