Credit: This is a review based on a lecture given by cardiologist, Dr Hendrik Zimmet, at The Melbourne Women’s and Children’s Update 2018.

 

Annual (Australian) Statistics: snapshot

Prevalence: > 400,000 (1.7%)

Mortality: 3,244 deaths

Incidence: 30,000 new cases

Hospitalisations: 51,000

Cost: $1 billion (2% health budget)

70% due to hospitalisation

10% pharmacotherapy

 

Impaired Cardiac Function (Heart Failure) is a syndrome inclusive of:

• Shortness of breath (NYHA class)
  • Orthopnoea
  • Paroxysmal nocturnal dyspnoea
• Peripheral Oedema
  • How high is the oedema?
    • Foot: 500 mL per limb
    • Lower leg: 1 L per limb
    • Thigh: 2-3 L per limb

Oedema above the level of the knees predicts significant splanchnic oedema and subsequent poor oral absorption of frusemide in particular, from an oedematous gut. Such patients typically require intravenous frusemide to effect significant diuresis.

The syndrome of heart failure can be seen as a final common pathway from various pathophysiological starting points.

Heart Failure is traditionally classified according to whether ventricular function is reduced, more recently referred to as HFrEF (heart failure with reduced [LV] ejection fraction) and also known as systolic heart failure, or whether ejection fraction is preserved (HFpEF) and is essentially synonymous with diastolic dysfunction.

HFrEF is technically present when the left ventricular ejection fraction is under 50% (40%) — i.e. when the left ventricle ejects less than half of its blood volume during systole. HFpEF, therefore, refers to a reduced ability of the heart to fill (during diastole) because of impaired myocardial relaxation (literally, a stiffened heart).

No matter how firm your (physical) body and sharp your mind, try to keep a supple heart.

Echocardiography then is the critical investigation, giving information relating to:

• Cardiac size and compliance
• Systolic and diastolic function
• Left vs right side
• Pulmonary pressures
• Valves
• Pericardium

Ventricular muscle that is under strain produces brain natriuretic peptide (BNP). BNP assays may prove useful in diagnosing a dyspnoea of uncertain cause. But only NT-proBNP (a test that is not covered under the national health scheme, Medicare) and not BNP or proBNP can be used to monitor progress in patients on ARNIs, such as Entresto (see later).

Cardiac Magnetic Resonance is also highly accurate at depicting cardiomyopathy, sensitively detecting myocardial oedema and inflammation but also patterns of fibrosis—such as ischemia, dilated cardiomyopathy, hypertrophic cardiomyopathy, and other aetiologies, each of which correlate with a characteristic appearance on MR imaging and patterns of fibrosis, in turn, with arrhythmia risk (another matter for another day).

Tiers in Heart Failure Therapy

Treat underlying cause: non-pharmacological management

• Fluid intake
• Salt intake

Pharmacotherapy

• Diuretics
• Beta-Blockers (especially women)
• ACE-Is
• ARBs
• MNARBs
• NPRs

Devices

• ICDs (women 3 x less likely to receive one)
• Cardiac Resynchronisation (CRT) including bi-ventricular pacing

Cardiac Rehabilitation and Multidisciplinary Care

Transplantation (and mechanical circulatory support)

Surgical therapies for advanced HF, such as high-risk CABG, mitral valve repair, left ventricular assist device implantation, and cardiac transplantation, are far less likely to be used in women.

Mortality in HF ³

• 4-7% in-hospital
• 10% 30-day
• 20% 1-year
• Up to 50% 5-years

Women tend to get heart failure at a later age than men and more typically have preserved systolic function (less coronary artery disease) and, consequently, a better (“preserved”, if you will) survival.

But women tend to be more symptomatic and, consequently, tend to have higher rates of hospitalisation.

Diabetes mellitus here, however (as elsewhere), is the great leveller. Diabetes seems to attenuate the protective vascular effect afforded by oestrogens to women. Oestrogens improve myocardial calcium handling and nitric oxide synthesis while reducing matrix turnover and down-regulating the renin-angiotensin-aldosterone system.

Optimal Fluid Balance management ³

• 1L of fluid = 1 kg bodyweight
• Daily weighs / patient diary: track and record fluid intake for 1 week until a routine is established [Note: routines generally about 3 weeks to become entrenched]
• Fluid restriction of 1.5 L per day is critical but only necessary in patients with problems of fluid overload
• Medical review required if weight increases > 1 kg/day in two successive days or more than 2.5 kg in a week
• Treat congestion – euvolaemia is king

Marvel at the improved survival in HFrEF over time with the introduction of newer therapies:

Reduction in relative risk of mortality vs placebo

• ACE-I: 16% (SOLVD)
• ARB: 17% (CHARM-Alternative)
• Beta-Blocker: 34% (CIBS-II)
• MRA: 30% (RALES)

Significant mortality remains, however.

Adding Ivabradine (Coralan)

• Sinus node inhibitor, reduces heart rate
• For those intolerant—or on maximum tolerated dosage with HR > 70 bpm— of beta blockers (SHIFT)
  • LVEF < 35%
  • HR > 70 bpm

Angiotensin Receptor Neprilysin inhibitor (ARNI) ³

Paradigm-HF Trial – Results Summary ¹

Primary Outcome

• 20% CV death or HF hospitalisation with LCZ696 compared with enalapril
  • 20% CV mortality
  • 21% HF hospitalisation

Secondary Outcome

• 16% reduction in all-cause mortality with LCZ696 vs enalapril
• LCZ696 superior to enalapril in reducing symptoms and physical limitations of HF
• No significant difference in incidence in new onset AF between treatment groups
• No significant difference in protocol-defined decline in renal function between treatment groups

Therapeutic Algorithm for Symptomatic HFrEF ²

2016 ESC Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure

Diastolic Heart failure (HFpEF) Management

Entresto (sacubitril / valsartan)

Use of and side effect profile of Entresto is similar to ACE-I and ARBs, with two exceptions:

• 36-hour washout period between ACE-I
• Additional, and user-variable, diuretic effect

Optimal Dosing

Clinical trial evidence gestures toward maximum tolerated dose

Up-titrate as tolerated

Which drug first?

• Relieve symptoms
• Combination better than single agent
• Trials suggest outcomes equal whether ACE-I/ARB or beta-blocker first

Dealing with Side Effects

Most common

• Reduced BP, elevated K, increased Cr/Ur
• Reduced HR (only with beta-blockers and Ivabradine)

See if another non-HF medication can be reduced or ceased – e.g. slow K, amlodipine, even diuretic (in patient on Entresto)

If no other option, consider reducing another HF medication or NPR inhibitor, even ceasing it, if it comes to that.

SGLT2 Inhibitors

• Empagliflozin demonstrated unprecedented 38% ↓ CV mortality in patients with diabetes
• Highly significant reductions in HF hospitalisations and end-stage kidney disease
•  1% reduction HbA1c levels, with favourable reductions in both BP ( 3-6 mm Hg) and body weight (2-4 kg/m²)

Additional Observed Effects

• Induces plasma volume contraction without activation of the sympathetic nervous system
• Might improve efficiency of myocardial energetics
• Decreased vascular stiffness and improved endothelial function
• In future, might even be considered in HF or chronic kidney disease patients without diabetes

A Vulnerable Period

30% readmission rate within first 30 days

Early review post discharge

Cardiac rehab

Many patients (24% in European data) are discharged with unresolved congestion, associated with poor long-term outcomes: 1-2 signs 33% and 3-5 signs 59% rehospitalisation within 30 days cf. 13% without signs of congestion. This, in turn, relates to poor patient compliance regarding daily weighs, fluid restriction, and medications.

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References

1. McMurray, J. J. et al. (2014) Angiotensin–Neprilysin Inhibition versus Enalapril in Heart Failure. The New England Journal of Medicine. [Online] 371 (11), 993–1004.
2. Seferovic, P. M. et al. (2019) Clinical practice update on heart failure 2019: pharmacotherapy, procedures, devices and patient management. An expert consensus meeting report of the Heart Failure Association of the European Society of Cardiology. European Journal of Heart Failure. [Online] 21 (10), 1169–1186.
3. Zimmet, Hendrik. Heart failure in Women. The Melbourne Women’s and Children’s Update 2018

Other works cited

Burdorf, Adam. Heart Failure in 2017: What’s New, What Matters and What’s Coming. University of Nebraska Medical Centre

For medical enquiries to Novartis Pharmaceuticals, call 1800 671 203 from anywhere in Australia or email medinfo.phauno@novartis.com.

Downloads

• Sacubitril_w_Valsartan_fact_sheet
• ACE Inhibitors – Australian Medicines Handbook
• HTN – ACEI, ARB, or DRI (AHRQ, 2011)
• ARNI vs Enalapril_nejm(2014)
• CHF, Decompensated-Rapid Optimization_Strategies for the ED(2002)
• ESC_HF 2019 Guidelines