Evidence limited, clinical skills paramount

Thursday, 27 Oct 2016

Approximately half of patients with heart failure have preserved left ventricular ejection fraction (HFPEF) yet there are limited treatment options that offer long term benefit.

Professor Andrew Sindone, Director of the Heart Failure Unit and Department of Cardiac Rehabilitation at Concord Hospital in Sydney, told the limbic that the onus is on physicians to focus on short-term symptomatic relief, and careful assessment and management of comorbidities.

“Cardiologists need to be ‘smart’ in improving the quality of life of their HFPEF patients,” he says.

“Heart failure is essentially a clinical diagnosis based on shortness of breath, fatigue, peripheral oedema and pulmonary congestion on chest X-ray,” he says.

“Often it’s only afterwards, once we have stabilised the patient, that we find on echocardiography that the ejection fraction is normal.”

The high proportion of heart failure patients with preserved rather than reduced ejection fraction was confirmed in the recent NSW HF Snapshot Study.1 A total of 42% had HFPEF, defined by a left ventricular ejection fraction of 50% or more at their most recent echocardiogram.

Underlying causes

HFPEF is a heterogeneous condition. A patient may have a range of contributing factors including diastolic dysfunction (arising from myocyte dysfunction and passive diastolic stiffness), myocardial fibrosis, fluid retention, pulmonary hypertension, diabetes, obesity, anaemia, iron deficiency and deconditioning.2

“We know that structural changes contribute to the pathology of HFPEF,” Professor Sindone says.

“There are changes in the extracellular matrix that make up the majority of the heart’s mass, including increased collagen. Changes in a protein called titin are also emerging as an important contributor, and might eventually lead to new and effective therapies.”

Titin acts as a molecular ‘spring’ within myocytes to assist expansion and contraction. Phosphorylation of titin has been implicated in passive stiffness of cardiomyocytes, potentially leading to slow or incomplete relaxation of the ventricle.2

A study using biopsies obtained during CABG surgery found that patients with hypertension and HFPEF, compared to those with hypertension alone or neither hypertension nor HFPEF, had more collagen-dependent and titin-dependent myocardial stiffness.3

“These data suggest that the development of HFPEF depends on changes in both collagen and titin homeostasis,” it concluded.


Once a diagnosis of HFPEF is suspected, based on the classic presentation of heart failure but a normal ejection fraction, the first step is to exclude other possible causes, says Professor Sindone.

There are many potential causes but the most common include lung disease (whether obstructive or interstitial), pericardial disease and valvular heart disease.

“Myocardial ischaemia is also an important consideration, as diastole is a complex and active process that requires energy rather than simply relaxation of the ventricle.

“HFPEF can also be mimicked by depression, exacerbated by obesity, and precipitated by drugs including calcium channel blockers, pioglitazone and NSAIDs,” Professor Sindone says.

Formal diagnostic criteria for HFPEF include signs and symptoms of heart failure, objective evidence of diastolic dysfunction, disturbed left ventricular filling, the presence of structural heart disease, and elevated brain natriuretic peptides.2

Focus on comorbidities

Patients with HFPEF are more likely to be female, elderly and have multiple comorbidities compared to those with HFREF, Professor Sindone explains.

“In fact, about half will die from something other than heart failure, and their comorbidities are often the reason for their hospital admission” he tells the limbic.

Identifying and treating these comorbidities requires a comprehensive approach and ‘smart thinking’, in the absence of specific treatment for their underlying heart failure.

“For example, the patient might benefit from stenting, CABG or intensive medication to treat myocardial ischaemia, or treatment of their atrial fibrillation, valvular heart disease, aortic stenosis, anaemia (especially iron-deficiency anaemia), lung disease or renal impairment,” he says.

Approach to treatment

European Society of Cardiology guidelines on the management of heart failure highlight the limited data on treatments that can reduce morbidity and mortality in patients with HFPEF.4

They recommend diuretics to control sodium and water retention, and to relieve breathlessness and oedema.

They also recommend management of hypertension with betablockers, ACE inhibitors or ARBs, treatment of myocardial ischaemia with beta-blockers, and control of heart rate in the case of atrial fibrillation.

All these steps aim to improve symptoms rather than change the course of the disease.4

Most of the drugs that should be avoided in HFREF should also be avoided in HFPEF, with some exceptions including verapamil and diltiazem.

“In practice, we tend to treat patients with HFPEF as though they have a reduced ejection fraction, knowing that the outcomes are not likely to be as good,” Professor Sindone says.

“For example, we use diuretics, we stabilise blood pressure (aiming for a systolic pressure of 105-110 mmHg), and lower the pulse rate to about 60 beats per minute to improve left ventricular filling and coronary perfusion and maximise stroke volume. We also use ACE inhibitors and beta-blockers much the same as we do in HFREF.”

Clinical trials of HFPEF have been problematic because of the difficulties that can arise in making the diagnosis, the high rate of comorbidities that can complicate outcomes, and the heterogeneity of the patient population.

“In addition, most trials enrol patients on hospital admission and who also have elevated BNP. These are the sickest patients, and perhaps less likely to experience longer-term benefit,” he says.

Professor Peter Macdonald, from St Vincent’s Hospital in Sydney, noted in a viewpoint published six years ago that HFPEF treatment was largely empirical and aimed to control associated conditions such as hypertension and symptoms and signs of fluid retention5 – and little appears to have changed.

He asked whether it was important to distinguish HFPEF from HFREF.

“Are they simply different ends of a continuous disease spectrum, or do they represent distinct entities with different causes and different natural histories? Given that they present with the same clinical syndrome, should they be treated the same way?

“These are important questions for which we currently lack answers.”

A recent review of HFPEF treatment strategies noted that a ‘one-size-fits-all’ approach may not be effective in this heterogeneous syndrome.2

“This concept is the critical element that has doomed many past clinical trials,” it said.2 “HFPEF encompasses a broad patient population, reflecting many comorbidities and pathophysiological processes.”

Another review summarised the existing clinical trial evidence in HFPEF.6 In brief:

  • Treatments with neutral results include sildenafil (aiming to prevent cardiac and myocyte remodelling), as well as ACE inhibitors, ARBs, endothelin antagonists and metalloproteinase inhibitors.
  • Evidence for the benefit of spironolactone is inconclusive. In the TOPCAT study benefits were observed in patients recruited in North America, but not those enrolled in Russia and Georgia. “Methodological problems, including the enrolment of patients outside North America who did not have heart failure or did not take the treatment, have been suggested,” Professor Sindone says.
  • Beta-blocker trials have failed to provide conclusive results in HFPEF. However, a prespecified subgroup analysis of the SENIORS study of nebivolol demonstrated a similar reduction in the primary endpoint of all-cause mortality and cardiovascular hospitalisations in patients with HFPEF as in those with HFREF.7
  • Other treatments “with promise” include those targeting advanced glycation end-products, statins to prevent the development of cardiac hypertrophy and reduce fibrosis, and the angiotensin-neprilysin inhibitor LCZ696. LCZ696 was shown to be superior to enalapril in reducing the risks of death and of hospitalisation for heart failure in patients with reduced ejection fraction in the PARADIGM-HF study,8 and is now being trialled in HEFPF in the PARAGON-HF study.9 Ivabradine to reduce heart rate in patients with HFPEF is being assessed in the ongoing EDIFY trial.10
  • The EMPA-REG OUTCOME trial showed that treatment of patients with type 2 diabetes using the SGLT2 inhibitor empagliflozin, which increases urinary excretion of glucose, significantly reduced the rate of heart failure hospitalisation or cardiovascular death in the total study population, compared to placebo.9 Consistent effects of empagliflozin were observed across subgroups defined by baseline characteristics, including in patients with, vs without heart failure. However, the data did not allow the outcomes to be analysed by pre-existing ejection fraction.

“The effect of empagliflozin is now being studied in nondiabetic patients with HFPEF to assess whether it may also benefit this group,” Professor Sindone said.

“In the next five years I suspect we might see more use of ivabradine to slow the heart down in HFPEF patients, as well as the use of the angiotensin-neprilysin inhibitor and a recommendation to consider empagliflozin in patients with type 2 diabetes.

“In the meantime, we will continue to have difficulty specifically treating HFPEF because of a lack of data, and we will rely on treating it as if patients have reduced ejection fraction but accepting that there may be less success.” Professor Sindone said.

We must also continue to assess and investigate our patients very carefully to make sure we are not missing treatable comorbidities that worsen their HFPEF.”



  1. Newton PJ et al. Acute heart failure admissions in New South Wales and the Australian Capital Territory: the NSW HF Snapshot Study. Med J Aust 2016; 204: 113.
  2. Senni M et al. New strategies for heart failure with preserved ejection fraction: the importance of targeted therapies for heart failure phenotypes. Eur Heart J 2014; 35 :2797-815.
  3. Zile MR et al. Myocardial stiffness in patients with heart failure and a preserved ejection fraction: contributions of collagen and titin. Circulation 2015; 131: 1247-59.
  4. McMurray JJ et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur Heart J 2012; 33: 1787-847.
  5. Macdonald PS. Heart failure with preserved ejection fraction – coming to terms with an oxymoron. Med J Aust 2010; 192: 4-5.
  6. Ferrari R et al. Heart failure with preserved ejection fraction: uncertainties and dilemmas. Eur J Heart Fail 2015; 17: 665-71.
  7. van Veldhuisen DJ et al. Beta-blockade with nebivolol in elderly heart failure patients with impaired and preserved left ventricular ejection fraction: Data From SENIORS (Study of Effects of Nebivolol Intervention on Outcomes and Rehospitalization in Seniors With Heart Failure). J Am Coll Cardiol 2009; 53: 2150-8.
  8. McMurray JJ et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med 2014; 371: 993-1004.
  9. Fitchett D et al. Heart failure outcomes with empagliflozin in patients with type 2 diabetes at high cardiovascular risk: results of the EMPA-REG OUTCOME trial. Eur Heart J 2016 Jan 26. pii: ehv728.
  10. Komajda M, Lam CS. Heart failure with preserved ejection fraction: a clinical dilemma. Eur Heart J 2014; 35: 1022-32.

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