One to two percent of the population is in heart failure, up to 10% of octogenarians, with a poor prognosis left untreated. Although recent pharmacotherapeutic advances have reduced re-hospitalisation rates to 44% at 12-months and also improved life expectancy, five-year mortality remains at 50%.¹
Clinically, heart failure is classified according to relative stroke-volume preservation about a median left ventricular ejection fraction (EF) of 40-49% and signs of diastolic dysfunction so that heart failure describes a complex clinical syndrome characterised by the heart’s inability to pump enough blood to meet the body’s metabolic requirements or it does so only at the cost of abnormally elevated diastolic volumes and pressures.¹
Simplifying one arm of the therapeutic approach, Dr Mariell Jessup reflects that:
Because 90% of patients in heart failure are volume overload, almost everybody gets a diuretic—whether they have low EF or normal EF heart failure. But you don’t have to continue the diuretic in every single patient, because more effective therapies can be instituted.²
First-line treatment of new-onset heart failure is medical therapy:
- Beta-blockers (BB)
- ACE Inhibitors (ACE-I) or angiotensin-II receptor blockers (ARB) – recommended in all reduced EF patients
- Loop Diuretics
Mineralocorticoid receptor antagonists (MRAs) are now considered part of first-line treatment for all symptomatic reduced EF patients, and appear to be the diuretic of choice in heart failure.
By all means, stabilise the patient. But clinicians ought to restrain themselves long enough to consider two questions that raise the possibility of treating the underlying cause; always preferable situation for in patient in front of you, before committing to further drug treatment:
- What risk factors, such as hypertension, does this patient have and can we manage them and what triggered this patient to be in heart failure (e.g. active ischaemia cf. prior infarction) and can I correct that?
- Is this poorly contractile or is this contraction-preserved heart failure? The answer to that is obtained from echocardiographic evaluation:
- Poorly contractile: low ejection fraction, dilated heart ≡ HFrEF (heart failure reduced ejection fraction) ≅ systolic heart failure
- Preserved contraction: normal ejection fraction, non-dilated heart ≡ HFpEF (heart failure preserved ejection fraction) ≅ diastolic heart failure
Because we find, continues Dr Jessop, that:
As a result of an ‘initial’ cardiac injury, structural, neurohumoral, cellular and molecular mechanisms are activated to maintain haemodynamic functioning, which leads to volume overload, increased sympathetic activity, cardiac remodelling and inflammatory processes that result in a vicious circle with a constantly aggravating progression.²
Short-term compensatory neurohumoral mechanisms become counterproductive in the long term.
Reduced Ejection Fraction: HFrEF
“Reduced” ejection-fraction (rEF) heart failure is a failure of the heart muscle’s contractility. Nuanced HFrEF therapy aims to get the patient on a small amount of all three of Beta Blockers, ACE-I or ARBs, and Aldosterone Receptor Antagonists.
These drug-classes make people feel better and make them live longer. One option is to start beta-blockers and ACE-I (or ARBs) together at a low dose and wait a few days before commencing AAs [MRAs]—and slowly, over subsequent weeks, titrate up the drugs. Notably, diuretics are not part of maintenance therapy in patient’s with a purely systolic heart failure.
Preserved Ejection Fraction: HFpEF
Normal or “preserved” ejection-fraction (pEF) heart failure is a failure of the heart’s relaxation or filling. There are distinct forms of HFpEF, such as exercise-induced diastolic dysfunction, chronic volume overload, and right heart failure/pulmonary hypertension:
A variable combination of drugs may be appropriate, with the three used in HFrEF seemingly less effective here and without clear reductions in mortality. Diuretics do help with symptom control. Apart from calcium-channel blockers, drugs contraindicated in HFrEF are also contraindicated in HFpEF. Control risk factors and comorbidities. Cardiac rehabilitation (exercise programs) are helpful:
Others:
- Ivabradine
- Bendavia
- PDE5 inhibitors
- Neprilysin inhibitors
- Endurance exercise
Beta-blocker (BB)
There are three beta-blockers that have been shown to improve survival:
- carvedilol 3.125 mg bd → 25 mg bd
- metoprolol succinate (not tartrate) 12.5-25 od → 200 od
- bisoprolol 1.25 mg od → 10 mg od
ACE Inhibitor (ACEi)
A number of ACE-I have been shown in trials to be effective, take your pick:
- benazepril (Lotensin)
- captopril (Capoten) 6.25 mg tid → 50 mg tid
- enalapril (Vasotec) 2.5 mg bd → 10-20 bd
- fosinopril (Monopril)
- lisinopril (Prinivil, Zestril) 2.5-5.0 mg od → 20-35 mg od
- perindopril (Aceon)
- quinapril (Accupril)
- ramipril (Altace) 2.5 mg od → 10 mg od
- trandolapril (Mavik)
Angiotensin Receptor Blocker (ARB)
- candesartan (Atacand) 4-8 mg od → 32 mg od
- eprosartan (Teveten)
- irbesartan (Avapro)
- losartan (Cozaar) 50 mg od → 150 mg od
- olmesartan (Benicar)
- telmisartan (Micardis)
- valsartan (Diovan) 40 mg bd → 160 mg bd
Mineralocorticoid (Aldosterone) Antagonist (MRA)
spironolactone — androgenic side effects such as painful gynaecomastia and decreased sexual drive 25 mg od → 50 mg od
In contrast to eplerenone, spironolactone is a non-selective MRA that additionally activates progesterone and androgen receptors, leading to gynaecomastia, … [decreased sexual drive] … and menstrual disorders, which are frequent causes of non-adherence. In addition, the blood pressure-lowering effect is stronger with spironolactone than with eplerenone.²
eplerenone — much less androgenic effects 25 mg od → 50 mg od
MRA should be used carefully in patients with advanced renal dysfunction or existing hyperkalaemia (potassium >5.0 mmol/l). Renal markers and electrolytes should be supervised regularly.²
Otherwise, consider a potassium-exchange resin such as patiromer, to supplement ACE-I / ARB / MRA treatment hyperkalaemic patients.
In patients who remain symptomatic despite these measures, consider adding an angiotensin receptor / neprilysin inhibitor (ARNI).
Angiotensin Receptor / Neprilysin Inhibitors (ARNI)
LCZ696 is a combination of the ARB valsartan and the neprilysin inhibitor sacubitril. Neprilysin (syn. neutral endopeptidase, NEP) is an endopeptidase that degrades natriuretic peptides and several other vasoactive substances (e.g. bradykinin, endothelin-1, adrenomedullin).²
References
- Berliner, Dominik & Bauersachs, Johann (2019) New drugs: big changes in conservative heart failure therapy? European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery. [Online] 55 (Supplement_1), i3–i10.
- Annals of Internal Medicine podcast: interview with Dr Mariell Jessup MD – February 16, 2011
- Heart Failure Medications – WebMD
Further Reading
- Sanderson JE. HFNEF, HFpEF, HF-PEF, or DHF: What Is in an Acronym? JCHF. 2014;2(1):93-94
- EMCrit Podcast 1: Sympathetic Crashing Acute Pulmonary Edema, Scott Weingart – June 10, 2012
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Heart failure with preserved ejection fraction: a clinical dilemma. EurHeartJ. 35; 16: 1022 – 1032
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Little WC, Zile MR. HFpEF: Cardiovascular Abnormalities Not Just Comorbidities. Circulation: Heart Failure. 2012; 5: 669-671
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. Heart failure and left ventricular remodelling in HFrEF and HFpEF. EurHeartJ. Vol 37; 5: 423 – 424
