Management of heart failure with preserved ejection fraction.

Heart failure with preserved ejection fraction is a highly heterogenous disease. There is emerging evidence that treatment should be tailored to the individual’s associated comorbidities No current algorithms exist for the management of heart failure with preserved ejection fraction. Conventional therapies used in heart failure with reduced ejection fraction are yet to show a mortality benefit Key treatment objectives include control of hypertension and fluid balance Common comorbidities include coronary artery disease, atrial fibrillation, obesity, diabetes, renal impairment and pulmonary hypertension. These comorbidities should be considered in all patients and treatment optimised (c) NPS MedicineWise 2020.

Introduction

Heart failure usually presents as exercise intolerance due to exertional dyspnoea. It is categorised according to left ventricular ejection fraction:

heart failure with preserved ejection fraction (HFpEF, also known as diastolic dysfunction)

heart failure with reduced ejection fraction (HFrEF).

Heart failure affects over half a million Australians and accounts for 1.6% of all hospitalisations. Approximately half of these cases are due to HFpEF. Despite sharing the same clinical symptoms, patients with a preserved ejection fraction tend to be older, more frequently female and obese, and have higher rates of comorbidities compared to those with a reduced ejection fraction.1-3

Although there have been significant advances in the management of HFrEF with several pharmacologic and device-based therapies recommended by guidelines, the current therapeutic options in HFpEF may alleviate symptoms but do not significantly reduce mortality.

Pathophysiology

Despite the marked differences in systolic function, patients with preserved ejection fraction and reduced ejection fraction can share the same level of functional impairment. Echocardiography is therefore vital to differentiate between them. Myocardial stiffening, reduced left ventricular compliance and impaired relaxation in diastole are characteristic,4 although peripheral mechanisms have also been implicated, such as impaired oxygen uptake and remodelling of skeletal muscle. Myocardial stiffening results in elevated left ventricular pressures during filling, with

further transmission to the left atrium and consequent pulmonary hypertension. This in part leads to the sensation of breathlessness. Left atrial myopathy is associated with worse haemodynamic features, likely due to a greater transmission of pressure.5

When considering HFpEF, it is important to exclude infiltrative cardiomyopathies. Approximately 13% of patients with HFpEF have cardiac amyloidosis. Patients with significantly increased wall thickness, low Doppler velocities, early-onset bilateral carpal tunnel syndrome, and other systemic manifestations of amyloidosis should undergo more detailed evaluation. Both cardiac MRI and nuclear imaging studies provide non-invasive methods of diagnosis.

Diagnosis

The diagnosis of HFpEF is challenging, in part due to clinical heterogeneity and the primary manifestation of symptoms and abnormalities, often with exertion. The condition is defined by a left ventricular ejection fraction of at least 50%, in combination with elevated biomarkers (either BNP or NT-proBNP) and echocardiographic features of structural or functional impairment.1,6 Up to 15% of patients can have normal natriuretic peptide measures at rest, and the sensitivity of resting echocardiography is limited. Although multiple echocardiography criteria exist, including an elevated E/e’ and left ventricular mass index, the presence of an enlarged left atrium, with a preserved ejection fraction and normal mitral valvular function, should prompt consideration of HFpEF.

The H2FPEF score, which combines clinical and echocardiographic characteristics, is a useful and clinically validated screening tool for patients presenting with dyspnoea (Table).7 It can help guide clinicians to refer patients on for exercise-based evaluation, either with invasive haemodynamics or diastolic stress testing with echocardiography.

Table

Screening tool for heart failure with preserved ejection fraction in patients with dyspnoea

	Clinical variable	Values	Points
H2	Heavy	Body mass index >30 kg/m2	2
	Hypertensive	≥2 antihypertensive drugs	1
F	Atrial fibrillation	Paroxysmal or persistent	3
P	Pulmonary hypertension	Echocardiographic estimated pulmonary artery systolic pressure >35 mmHg	1
E	Elderly	Age >60	1
F	Filling pressure	Echo derived E/e’ >9	1

H2FPEF score and point allocation: a diagnosis of HFpEF is likely with a total score ≥6, intermediate with a score of 2–5, and unlikely with a score of ≤1.

Source: Adapted from reference 7

Given the diverse spectrum of comorbidities associated with HFpEF, it is suggested that management be tailored to these comorbidities.8-10 Distinct comorbidity phenotypes have been identified with differing long-term outcomes across groups.8 Hypertension, fluid retention, obesity and metabolic syndrome, pulmonary hypertension, cardiac fibrosis and ischaemia, and renal impairment have been identified as treatment targets (and the key determinants of phenotype) in patients with HFpEF.11

Management

General principles for the management of HFpEF are outlined in the Box.12 Structured weight-loss programs and exercise-based rehabilitation are recommended, as well as adequate control of comorbidities such as hypertension, and particularly atrial fibrillation and diabetes.

Non-drug interventions

Salt and fluid restriction are advised in HFpEF, although evidence for benefit is lacking.4,13 Cessation of smoking, limiting alcohol intake and a high-fibre diet are advised.14 Exercise training appears to improve exercise capacity and quality of life.15 There is a dose-dependent decrease in the risk of HFpEF with a lower BMI and increasing exercise. However, the amount of exercise needed to be beneficial may be greater than standard recommendations. Further studies are in progress.16

Pharmacotherapy

In contrast to HFrEF, ACE inhibitors, angiotensin receptor antagonists (sartans), aldosterone antagonists, beta blockers and digoxin have not shown a mortality benefit in HFpEF.17-22 However, study populations in the trials were variable because of varying definitions of the disease and difficulty in confidently diagnosing HFpEF. This clouded interpretation of the results.23 In the absence of conclusive data, pharmacotherapy for HFpEF varies widely.

Neurohormonal antagonists

Hypertension is a major risk factor for HFpEF.1 Blood pressure management is paramount, and an ACE inhibitor or angiotensin receptor antagonist is appropriate.6 Despite not having a significant mortality benefit, perindopril, candesartan and spironolactone may have value in reducing the risk of hospitalisations from heart failure through inhibition of the renin–angiotensin–aldosterone system.17-19

The TOPCAT trial assessed 3445 patients with HFpEF (with an ejection fraction over 45%). Despite an overall negative outcome, later investigation found significant geographical heterogeneity in outcomes. Patients from Russia and Georgia appeared not to have the structural and functional features of a preserved ejection fraction. When they were removed from the analysis, spironolactone reduced hospitalisations. The PEP-CHF trial assessed the role of perindopril, with a weak signal of reduction in hospitalisation.17

Care must be taken to monitor for renal dysfunction and hyperkalaemia when starting spironolactone, particularly as renal dysfunction is prevalent in people with HFpEF. A combination of multiple antihypertensives may be needed to adequately control blood pressure, with ambulatory blood pressure monitoring providing the most accurate measure of control.

Diuretics

Diuresis helps lower left ventricular pressures, reducing pulmonary congestion and improving symptoms.24 Furosemide (frusemide), a loop diuretic, is most commonly used. Patients with preserved ejection fraction are often more sensitive to diuresis than those with reduced ejection fraction and are at greater risk of developing renal dysfunction and hypotension.

Statins

Aside from their cholesterol-lowering benefits, statins also target systemic inflammation.25 This is an important contributor to the pathogenesis of HFpEF. Their use has been associated with lower mortality in these patients,26 even in those without coronary artery disease.27 However, further trials are needed to confirm these results and elucidate the mechanism of action.

Sacubitril with valsartan

Sacubitril with valsartan inhibits both neprilysin and the angiotensin AT1 receptor. In addition, neprilysin inhibition increases natriuretic and vasoactive peptides, leading to natriuresis, diuresis and vasodilation.28 Although a significant reduction in mortality was seen with the combination in HFrEF, the recent PARAGON-HF trial29 found it did not significantly reduce hospitalisations and mortality in patients with HFpEF.30,31

Managing comorbidities

Patients with HFpEF frequently display cardiac and non-cardiac comorbidities including coronary artery disease, hypertension, obesity and diabetes.1-3 Some experts believe these extra-cardiac comorbidities lead to systemic inflammation, a key driver in the development of HFpEF.32 These comorbidities must be considered as part of the initial evaluation, and aggressively managed.

Obesity

Obesity is associated with diastolic dysfunction and worse left ventricular remodelling.33,34 Patients with obesity have increased epicardial fat, limited cardiac reserve, worse pulmonary vascular disease and greater biventricular remodelling.35 Observational studies support the benefit of weight loss and exercise in improving quality of life and survival.36 Caloric restriction is well tolerated and significantly improves heart failure symptoms and exercise capacity.37

Type 2 diabetes

Tight glycaemic control is important and metformin is the first-line oral hypoglycaemic drug.6 Sodium-glucose co-transporter 2 inhibitors have shown significant benefits in HFrEF, reducing mortality in patients with and without diabetes.38,39 These drugs may be beneficial in HFpEF by inducing osmotic diuresis, natriuresis and weight loss, and reducing heart failure hospitalisations and all-cause mortality.40 Several trials are currently assessing outcomes in HFpEF.41

Renal impairment

HFpEF commonly co-exists with renal dysfunction, in part due to shared comorbid risk factors such as aging, hypertension and diabetes, and to the adverse haemodynamics promoting cardiorenal syndrome.42 In patients with a comorbid chronic kidney disease phenotype, cardiorenal syndrome appears to result from renal venous congestion due to pulmonary hypertension and right ventricular dysfunction.8 In these cases, careful diuresis may be required, and haemodynamic monitoring may be helpful to titrate therapy.43

Atrial fibrillation and rate control

Atrial fibrillation co-exists in approximately one-third of patients with HFpEF,44 and may precede or follow the development of heart failure.45 Patients with atrial fibrillation display elevated filling pressures and reduced cardiac output. The loss of atrial contraction in late diastole compounds the impaired left ventricular filling. As a result, the atrial myopathy promotes atrial fibrosis and higher transmission of left ventricular pressures onto the pulmonary circulation.46 In suitable candidates, rhythm control should be considered in view of the potential benefits, although trial data are lacking. If this fails, traditional management principles apply, with long-term rate control and anticoagulation. Catheter ablation appears safe, with similar functional improvements and rates of recurrence as in patients with HFrEF.47 Further studies are in progress.48

Rate control has also been suggested as a treatment target for patients in sinus rhythm to maximise diastolic filling. An increased heart rate is associated with cardiovascular death and hospitalisation in HFpEF,49 although pharmacological rate control has yet to show a mortality benefit.50,51 It may even be detrimental to the patient’s exercise capacity52 as it exacerbates their inability to compensate for exercise demands by inducing chronotropic incompetence.53 For this reason, adaptive atrial pacing has been suggested as an alternative to pharmacological rate control.54

Coronary artery disease

Coronary artery disease affects over half of patients with HFpEF and is associated with increased mortality.55 The symptom of exertional dyspnoea may indicate angina, and current recommendations advise exclusion of coronary disease. The decision for revascularisation is independent of the HFpEF diagnosis, and should be considered where appropriate.55

Right ventricular dysfunction

Chronic pulmonary hypertension, driven by persistent elevations in left-sided pressures, can lead to right ventricular failure in HFpEF.56,57 These changes are typically seen later in the course of the disease and indicate a worse prognosis. Preliminary results with milrinone are promising, but further trials of these therapies are required.58

Drugs to avoid

Avoiding or minimising the use of non-steroidal anti-inflammatory drugs is recommended in heart failure, due to their association with sodium and fluid retention and increased risk of renal impairment and hospitalisations due to heart failure.59

Glitazones are not recommended due to the risk of worsening heart failure related to salt and water retention.60 Despite being associated with worse outcomes in HFrEF, non-dihydropyridine calcium channel blockers appear safe to use in patients with preserved ejection fraction, although they are not necessarily beneficial.61

The combination of ACE inhibitors and neprilysin inhibitors can lead to angioedema, and they should not be used within 36 hours of each other.6,62 A randomised controlled trial of isosorbide mononitrate demonstrated a worsening of exercise capacity, and is not recommended for HFpEF. Sildenafil has also been rigorously tested in several randomised trials and has not shown harm or benefit.63

Devices

The lack of benefit from drug therapies is likely due to the myriad of pathways activated in HFpEF, with the only definite uniting pathology being elevated left ventricular filling pressures. Consequently, devices targeting this pathway have been tested in trials over the past few years.

Interatrial septal device

A transcatheter interatrial left to right shunt has been shown to offset the high left atrium pressure that develops in HFpEF.64-66 One-year observational outcomes have shown the safety of this device, with increased exercise tolerance, quality of life, and a trend toward decreased hospitalisations and heart failure symptoms.67,68 A trial is under way.69

Implantable pulmonary arterial pressure monitoring

Continuous monitoring of haemodynamics through an implanted device allows for assessment of diastolic left ventricular pressures, and early appropriate administration of diuretics. The CHAMPION trial demonstrated reduced hospitalisations with this device by alerting physicians to high pulmonary pressures and directing subsequent changes to medicines.70,71 This device is available for clinical use, however it is currently limited by availability and cost.

Future directions

In HFrEF, there is substantial evidence of improved outcomes with multidisciplinary care (including GPs, cardiologists, specialist nurses and allied health).13 This approach should also be considered in patients with HFpEF. Clinics specialising only in HFpEF have shown benefits overseas, particularly in identifying ‘treatable’ forms of the condition such as amyloidosis, and in referring patients on to relevant clinical trials.72

Conclusion

HFpEF is a diagnostic and therapeutic challenge. Early identification of the disease along with aggressive control of comorbidities are key to management. Determining a patient’s associated comorbidities will allow targeted use of available therapies.

Avoid tachycardia	For patients with atrial fibrillation, use digoxin or beta blockers
Blood pressure control	ACE inhibitors, angiotensin receptor antagonists (sartans) or mineralocorticoid receptor antagonists may be of the greatest benefit
Comorbidities	Optimise cardiac and noncardiac conditions, particularly atrial fibrillation, obesity and diabetes mellitus
Diuretics	Use loop diuretics to relieve congestion, with close monitoring of renal function
Exercise training	Improves exercise capacity and quality of life
Source: Adapted from reference 12