Management of heart failure

Specific drug therapy for heart failure focuses on improving prognosis (using inhibitors of the renin–angiotensin–aldosterone system [RAAS] and sympathetic nervous system [SNS]) and achieving and maintaining euvolaemia to improve symptom status (using diuretics).

Activation of the RAAS and SNS has been found to be associated with pathogenesis and progression of the heart failure disease process, as well as with reduced survival.8,9 Blockade of these systems has revolutionised the management of heart failure (Box 2). Angiotensin-converting enzyme (ACE) inhibitors (or angiotensin receptor blockers [ARBs] in those unable to tolerate ACE inhibitors) and β-blockers are the cornerstone of drug therapy for systolic (ie, low ejection fraction) heart failure. These agents should be initiated at low doses and up-titrated to the target or maximal tolerated dose, as per guidelines.1 For both drug classes, blood pressure (lying and standing), heart rate, renal function and potassium levels should be regularly monitored. Particularly in patients receiving ACE inhibitors for the first time, and especially those with a history of hypertension, careful and early monitoring of renal function is imperative because of the small but real possibility of bilateral renal artery stenosis. In this clinical context, administration of ACE inhibitors (and ARBs) may lead to acute renal failure.

β-Blockers have their own specific side effects.23 Some agents (eg, carvedilol and nebivolol) also possess vasodilator properties, making them theoretically more difficult to initiate in patients with borderline blood pressure levels. However, in studies of patients with severe heart failure (eg, COPERNICUS15), carvedilol was extremely well tolerated, even with a baseline systolic blood pressure cut-off of 85 mmHg. Conversely, vasodilation may offset the tendency toward early worsening of heart failure. Highly selective β1-blocking agents (eg, nebivolol, bisoprolol) may be preferred in the setting of concomitant chronic obstructive pulmonary disease (COPD). COPD is not an absolute contraindication to β-blocker therapy in heart failure, provided that clinically significant reversible airflow obstruction is not present. This can be readily detected on lung function testing using pre- and post-bronchodilator spirometry.

Aldosterone receptor antagonists, in addition to background ACE inhibitor and β-blocker therapy, have been found to be beneficial across all severities of systolic heart failure.24 Survival benefits have been observed in patients immediately after myocardial infarction,18 in patients with mild symptoms of systolic heart failure,19 and in those with advanced symptoms17 (Box 2). For this reason, the most recent Australian guideline update1 recommended that aldosterone receptor antagonists be added to background ACE inhibitor and β-blocker therapy in all patients with systolic chronic heart failure who remain symptomatic despite the ACE inhibitor and β-blocker therapy. However, as combining RAAS blockers puts patients at increased risk of hyperkalaemia, hypotension and renal impairment, they should be carefully monitored for these side effects, especially during commencement of aldosterone-blocking therapy in patients with borderline hypotension, renal impairment or diabetes mellitus. In contrast, no benefit with either RAAS blockers or SNS blockade has yet been established for HFPEF.

Diuretics are primarily used to relieve symptoms through achievement and maintenance of euvolaemia. They have not been shown to provide prognostic benefit.25

Digoxin is the mainstay therapy to control ventricular response in patients with heart failure and atrial fibrillation. Its use in sinus rhythm has waned, particularly after the publication of the Digitalis Investigation Group (DIG) study, which demonstrated no overall prognostic benefit. However, further analysis of the DIG study suggested that patients receiving relatively small doses within a serum digoxin range of 0.5–0.8 ng/mL had improved survival, although this survival advantage was largely confined to men.26 Caution is needed with the use of certain concomitant medications because of the potential for pharmacodynamic interactions (eg, β-blockers leading to atrioventricular block) or pharmacokinetic interactions (eg, concomitant renal impairment leading to digoxin toxicity).

The combination of nitrates and hydralazine has been used for many years as an alternative to ACE inhibitors. However, ARBs are preferred in patients with intolerance to ACE inhibitors, as this drug class has been shown to be of benefit (Box 2).21 Amiodarone is commonly used in patients with heart failure and arrhythmias but has been found not to provide any specific prognostic benefit in these patients; thus its use is limited to treatment of the underlying arrhythmia.

The use of antiplatelet and anticoagulant therapy in heart failure is somewhat controversial. For patients with known ischaemic heart disease, aspirin and other antiplatelet agents should be continued. Warfarin should be reserved for patients with chronic heart failure and atrial fibrillation, although it is often prescribed (without supporting data) for patients with marked dilatation of their left atrium and/or ventricle because of concerns about an increased risk of thromboembolism.

The two main device-based therapies used in patients with heart failure are the implantable cardioverter defibrillator (ICD) and cardiac resynchronisation therapy (CRT). Key studies supporting their use are summarised in Box 3.

ICDs are indicated to reduce sudden death in high-risk patients — about half of patients with systolic heart failure die a sudden, presumed arrhythmic, death. Implantation of these devices is currently recommended for patients with a low ejection fraction (ie, ≤ 30% after myocardial infarction, irrespective of severity of symptoms, or ≤ 35% in other patients).1 In the Multicenter Automatic Defibrillator Implantation Trial II (MADIT-II),30 which established these criteria, there was a 5.6% absolute risk reduction in all-cause death over the mean 20 months of follow-up.

ICDs are almost invariably implanted in patients who also require CRT, as the indications overlap. CRT is indicated for patients with New York Heart Association (NYHA) Class III–IV symptoms of heart failure who are in sinus rhythm and have evidence of so-called ventricular dyssynchrony (ie, left and right sides of the heart are not contracting in a synchronous manner). Measurement of the QRS interval on ECG has been taken to be a rough surrogate for ventricular synchrony, with a QRS duration of ≥ 120 ms generally indicative of dyssynchrony. However, many patients with a prolonged QRS interval do not have dyssynchrony, and many with a normal QRS interval do have dyssynchronous ventricles. Because of this, echocardiographic-based criteria for dyssynchrony have been proposed to improve the sensitivity and specificity of the diagnosis, as well as potentially the response rates to therapy (currently about 70% of patients derive clinical benefit with CRT). In patients who do respond to CRT, early and marked symptomatic benefit can be seen. Studies such as the Cardiac Resynchronization — Heart Failure (CARE-HF) trial have shown a stand-alone prognostic benefit with CRT additional to background pharmacological therapy in NYHA Class III–IV patients who meet the above criteria.27 Absolute mortality risk was substantially reduced (by 7.1% over 2 years) in the CARE-HF trial.

More recently, studies of patients with less severe symp-toms (NYHA Class I-II) have also demonstrated benefit with CRT,28,29 but the benefit was mostly confined to pa-tients with a QRS interval ≥ 150 ms, hence the revised Australian guidelines reflecting this.1 Given the lower overall risk in these patients, absolute risk reduction was less than that observed in the CARE-HF trial.

Some newer approaches to treating heart failure have been developed, and these may provide ancillary benefit to the standard therapies described above.

In the GISSI Heart Failure study, use of fish oils (1 g/day of n-3 polyunsaturated fatty acids) was shown to provide a small but significant outcome benefit compared with placebo on the study’s primary end point of death, and time to death or admission to hospital for cardiovascular reasons in patients with symptomatic, primarily systolic, heart failure.32 In absolute terms, 56 patients needed to be treated for a median duration of 3.9 years to avoid one death. Side effects were minimal to non-existent.

Ivabradine, an agent that slows heart rate (additional to background β-blockade) has shown clinical benefit in the SHIFT study.33 Ivabradine is guideline-recommended,1 and has been approved by the Australian Therapeutic Goods Administration.

Anaemia and iron deficiency are relatively common in patients with heart failure. Definitive evaluation of raising haemoglobin levels using erythropoietin-stimulating agents in patients with anaemia and heart failure is ongoing.34 The Ferinject Assessment in Patients with Iron Deficiency and Chronic Heart Failure (FAIR-HF) trial showed that regular administration of intravenous ferric carboxymaltose improved symptom status and exercise tolerance in iron-deficient patients with heart failure.35 This led to the Australian guideline recommendation that iron deficiency should be looked for and corrected in patients with heart failure.1

Many patients with heart failure have additional concomitant cardiac disease. Amelioration of cardiac disease may relieve symptoms and improve the patient’s overall heart failure status. All patients with heart failure should be investigated for ischaemic heart disease, ultimately by coronary angiography. Correction of coronary disease using surgical approaches has not been shown to provide clinical benefit compared with optimal medical therapy overall in the STICH study.36,37

Control of chronic arrhythmias is another important component of heart failure therapy. In particular, the ventricular response to atrial fibrillation should be controlled, ideally to < 70 beats/min. Drugs such as β-blockers, digoxin and amiodarone may be useful in this regard.

Valvular heart disease should be investigated using echocardiography. Mitral regurgitation is commonly observed in heart failure, often due to dilation of the valve apparatus secondary to ventricular enlargement as part of the ongoing remodelling process. New percutaneous techniques have been developed to non-invasively minimise mitral regurgitation in the hope this will help minimise or even reverse remodelling, but these remain largely experimental. Similarly, percutaneous approaches to treating aortic stenosis are under active evaluation.

Australian guidelines recommend that patients hospitalised with an exacerbation of heart failure be referred to a heart failure program after discharge.1 This can be in the form of a heart failure home-visit program, heart failure exercise program, cardiologist outpatient clinic, or nurse-led or nurse practitioner clinic. Multidisciplinary ambulatory care programs targeting patients with heart failure reduce hospital readmission and mortality.38 These programs ideally involve a cardiologist, heart failure nurse, pharmacist, physiotherapist, dietitian, GP and psychologist. The main objectives of these programs are listed in Box 4. Ambulatory care heart failure programs are accessible at most tertiary hospitals and many community health centres in Australia.39

The frequency of follow-up outpatient appointments depends on the patient’s clinical status, as well as his or her ability to self-care and manage the heart failure. Patients who require optimisation of pharmacotherapy or further diagnostic investigations, who have been recently hospitalised, who are exhibiting signs and symptoms of an acute exacerbation or who require further assessment for device therapy or heart transplantation will need to be seen more often (even weekly) in a heart failure outpatient clinic or program. Patients with stable heart failure usually only require 3–6-monthly monitoring of their clinical status but should be referred to a heart failure exercise program. Patient education is vital and is usually provided by the heart failure nurse. Patient education provided to patients and carers should always be based on the Living well with chronic heart failure booklet developed by the National Heart Foundation of Australia.40

The focus of nurse-led clinics is primarily optimisation of pharmacotherapy and education. Patient and carer education focuses on disease, diet, exercise, medications, lifestyle issues and self-management strategies. Titration of medications may be done by a nurse practitioner or a heart failure nurse under the supervision of a cardiologist or through an approved titration protocol. A meta-analysis of nurse-led clinics has found an improvement in patient outcomes, including a reduction in hospital admissions and mortality.41

A growing area in the management of heart failure is the use of telemonitoring, particularly for patients in rural and remote areas who may not have access to ambulatory care heart failure programs. Telemonitoring involves the transmission of clinical data, such as blood pressure, weight and heart rate, through digital broadband, wireless, bluetooth or satellite technology.42 The data are transmitted to a hospital or health care facility where they are reviewed by a cardiologist or heart failure nurse, and appropriate treatment is implemented. Although telemonitoring is ideal for patients in rural and remote areas, it is not advocated for patients in metropolitan areas who have access to ambulatory care heart failure programs. The benefits of a face-to-face interaction have been shown to far outweigh the benefits of telemonitoring.43 Meta-analyses and systematic reviews of telemonitoring programs for heart failure have found that they reduce hospital admission and mortality.42,44 However, two subsequent large randomised controlled trials of telemonitoring found no significant effect on hospitalisation or mortality,45,46 raising questions about its efficacy. Further research is required.

Shared health care is a model of health care delivery in the primary care setting that involves collaboration among practitioners of different disciplines or with different skills and knowledge. For patients with heart failure, an ideal shared care model would involve collaboration between the GP and cardiologist, an allied health professional and/or heart failure nurse. The success of a shared care model is influenced by the quality of collaborative working relationships, as frequent communication between team members is essential. Shared care involving a cardiologist and GP for patients with heart failure has been shown to reduce mortality by 20% when compared with follow-up by a GP alone.47

There is also scope for general practice nurses to improve outcomes in primary and secondary prevention of heart failure in the community. This may be through an absolute risk clinic, where general practice nurses assess and educate patients about their risk of cardiovascular disease using the absolute risk tool recommended by the National Heart Foundation of Australia.48 Patient review by the GP would be short, focusing on prescription of evidence-based medications such as antihypertensive agents or statins. Similarly, general practice nurses could also run a heart failure clinic where they review patients and provide education about self-management. For these clinics to be successful, general practice nurses would require professional development in these areas.