Heart failure (HF) is a common clinical syndrome with ever-increasing prevalence in the Western world. It is associated with extensive morbidity and mortality, as well as being a significant burden on global healthcare systems with at least 26 million people affected worldwide (Savarese and Lund, 2017). According to the most recent National HF Audit in 2019, around 900 000 individuals have HF in the UK and the disease consumes up to 2% of the total NHS expenditure (McDonagh et al, 2019).
Thus, understanding the pathophysiology and the pharmacological treatment behind the failing heart is imperative in optimally managing the condition at an early stage, averting the potential downward spiral, and hence improving not only quality but also the quantity of life.
Heart failure
HF is defined by the American College of Cardiology/American Heart Association (ACC/AHA) as a complex clinical syndrome that occurs from any structural or functional impairment of ventricular filling or ejection of blood (Yancy et al, 2013). Ejection fraction (EF) represents the percentage of blood pumped out of the left ventricle of the heart with each beating. HF falls under two main groups: HF with reduced ejection fraction (HFrEF), also known as systolic dysfunction, and HF with preserved ejection fraction (HFpEF), also known as diastolic dysfunction (Yancy et al, 2013). According to ACC/AHA, HFrEF is indicated by an EF of ≤40%. It develops when the left ventricle fails to contract normally and to pump with the force needed to eject enough blood into the circulation (Yancy et al, 2013). It is important to note individuals with systolic dysfunction (HFrEF) generally have elements of diastolic dysfunction as well. HFpEF is indicated by EF of ≥50% and generally occurs due to long-standing high blood pressure that leads to thickening of the heart muscle, which results in impaired filling of the left ventricle (Yancy et al, 2013; McDonagh et al, 2019). Individuals with EF values between 40-50% represent an intermediate or borderline group. The focus of this article, unless indicated otherwise, is the pharmacological treatment of the most common type of HF, which is HFrEF.
The majority of HF cases, around two-thirds, occur in patients with underlying ischaemic heart disease (IHD) and typically these individuals have a history of previous acute myocardial infarction (AMI) (Butler, 2010). The other cases have non-ischaemic cardiomyopathy, which includes hypertension, arrhythmias, cardiomyopathies, respiratory disease, autoimmune disease, substance misuse and valvular heart disease (Butler, 2010; Easa et al, 2021).
Pathophysiology
The counter-adaptive haemodynamic mechanisms driven by the failure in pumping function (and thus reduction in cardiac output) are common regardless of the antecedent cause. These are elicited mainly via the unwanted activation of the sympathetic nervous system (SNS) and the renin-angiotensin-aldosterone system (RAAS) (Egbuche et al, 2020). In response to low effective arterial volume, the hormone renin is released from the kidneys, which then triggers the release of angiotensinogen from the liver (Persson, 2003). Renin cleaves angiotensinogen into angiotensin I (ATI). The angiotensin-converting enzyme (ACE) then converts ATI to angiotensin II (ATII). The central pathophysiology of ATII initiates through binding and activation of the angiotensin II receptor (type I) (Atlas, 2007). The activation of this cascade leads to changes that occur in the cardiovascular system (vasoconstriction, increased blood pressure, increased cardiac contractility, vascular and cardiac hypertrophy), the kidneys (sodium reabsorption), SNS and the release of aldosterone from the adrenal cortex (Atlas, 2007). When left to run unchecked, these counter-productive mechanisms will worsen the haemodynamic state of the patient, clinically worsening symptoms (eg fatigue, dyspnoea, peripheral oedema) and accelerating their ultimate decline. Knowing the pathophysiology of HF is fundamental for understanding the pharmacological treatment of HF, however, the fine details are beyond the scope of this report, but it has been covered in our previous article (Easa et al, 2021).
Pharmacological treatment
The focus in the pharmacological treatment of HF is directed towards the neurohormonal pathways, SNS and RAAS (see Figure 1), which have been recognised to be central in the pathogenesis of HF (Egbuche et al, 2020). Table 1 details some of the significant trials that have led to the recommended pharmacological treatments in common usage today. According to the National Institute for Health and Care Excellence guideline for the management of chronic HF (2018), individuals with reduced ejection fraction should be offered a beta-blocker and an angiotensin-converting enzyme inhibitor (ACEI).
Figure 1. The neurohormonal changes (renin-angiotensin-aldosterone system and the sympathetic system) occurring in patients with heart failure together with the main pharmacological treatments. ACEI, angiotensin-converting enzyme inhibitors; MRA, mineralocorticoid antagonist; ARB, angiotensin receptor blocker
Table 1. Summary of trials supporting the different pharmacological treatments used in heart failure
| Treatment type | Drug | Trial | Year | Reference |
|---|---|---|---|---|
| ACEI | Enalapril | SOLVD | 1992 | Yusuf et al, 1992 |
| Captopril | SAVE | 1992 | Pfeffer et al, 1992 | |
| Cardiac glycoside | Digoxin | Digitalis Investigation Group | 1997 | He et al, 1997 |
| MRA | Spironolactone | RALES | 1999 | Pitt et al, 1999 |
| Eplerenone | EPHESUS | 2003 | Pitt et al, 2003 | |
| β-blockers | Bisoprolol | CIBIS-II | 1999 | Dargie and Lechat, 1999 |
| Carvedilol | COPERNICUS | 2002 | Packer et al, 2002 | |
| ARBs | Valsartan | VALIANT | 2003 | Velazquez et al, 2003 |
| Candesartan | CHARM-Alternative | 2003 | Granger et al, 2003 | |
| HCN-channel inhibitors | Ivabradine | SHIFT | 2010 | Swedberg et al, 2010 |
| Angiotensin and neprilysin inhibitors | Valsartan and sacubitril | PARADIGM-HF | 2014 | McMurray et al, 2014 |
| SGLT2 inhibitors | Dapagliflozin | DAPA-HF | 2019 | McMurray et al, 2019 |
| Empagliflozin | EMPEROR-reduced | 2020 | Packer et al, 2020 |
ACEI, angiotensin-converting enzyme inhibitors; MRA, mineralocorticoid receptor antagonists; ARB, angiotensin receptor blocker; HCN, hyperpolarisation-activated cyclic nucleotide-gated; SGLT2, sodium-glucose co-transporter 2
Beta-adrenoceptor antagonists (β-blockers)
β-blockers, eg bisoprolol, carvedilol or metoprolol, licensed for HF are used as part of the first-line treatment, unless contraindicated (Böhm and Maack, 2000; British National Formulary, 2021). Treatment must be started at low doses and titrated slowly upwards, every 1-2 weeks, to the maximum tolerated dose. The gradual increase and monitoring are key in the treatment of HF, especially as some patients may feel worse during the initial stages. Additionally, if patients are stabilised on one of the other β-blockers (eg atenolol), for other existing conditions such as hypertension or angina, they should be switched to a β-blocker licensed for heart failure (NICE, 2018). Clinical improvement with β-blockers can take up to 3 months to become apparent (Butler, 2010). Moreover, it is imperative to inform diabetic patients that this treatment may cause hypoglycaemia as well as mask the symptoms of hypoglycaemia. Moreover, it is imperative to inform diabetic patients to monitor their blood glucose levels, since treatment with β-blockers can lead to fluctuations in their blood glucose levels, which can encourage hyperglycaemia, cause hypoglycaemia, or mask the symptoms of hypoglycaemia.
The benefit of using β-blockers in HF is to offer cardiac protection from excessive sympathomimetic stimulation, which would otherwise lead to poor prognosis (Böhm and Maack, 2000). The chronic norepinephrine elevation, in HF, leads to an increase in stimulation of the β-adrenergic system, which plays a significant role in cardiac inotropy. Over time this results in unfavourable remodelling of the heart, due to maladaptive mechanisms, which leads to tachycardia and decreased myocardial blood flow (Böhm and Maack, 2000). Thus, treatment with β1-adrenoceptor blockers is paramount in the long-term management of HF. As demonstrated in clinical trials, its use leads to a reduction in heart rate, improvement of cardiac remodelling, and also has antiarrhythmic effects (Böhm and Maack, 2000). Thus, studies have shown beneficial outcomes in terms of improvement of symptoms and ventricular function, but also a reduction in hospitalisation and mortality (Packer et al, 1996; Dargie and Lechat, 1999; Böhm and Maack, 2000).
Angiotensin-converting enzyme inhibitors (ACEIs)
ACEIs, eg ramipril, perindopril, enalapril, lisinopril, quinapril, fosinopril and captopril, have consistently shown across several large studies significant improvement in all-cause mortality with their use as the first-line treatment in the management of HF, unless contraindicated (Yusuf et al, 1992; Pfeffer et al, 1992; British National Formulary, 2021). The treatment should be initiated at low doses and titrated gradually at 2-weekly intervals to the target dose with renal function checked 2 weeks after initiation and after every dose increase. Monitoring and caution are advised for individuals with renal dysfunction and/or elevated potassium levels (Egbuche et al, 2020). Around 10% of patients will develop a dry cough due to bradykinin build up in the lung and 5% may need to switch to an angiotensin receptor blocker (ARB) due to this (Overlack, 1996).
ACEIs down-regulate the production of angiotensin II, from angiotensin I, and therefore aldosterone. This leads to beneficial downstream physiological effects on the cardiovascular systems; including a reduction in cardiac preload and afterload, as well as a reduction in systolic and diastolic blood pressure and the renal system with an increase in diuresis and natriuresis (Atlas, 2007).
Angiotensin receptor blockers (ARBs)
ARBs licensed for HF, eg candesartan, losartan, or valsartan, are considered as an alternative therapy if ACE inhibitors are not tolerated (British National Formulary, 2021). Due to a subtly different mechanism of action, ARBs have a different side effect profile with a lower incidence of dry cough and a much lower incidence of angioedema compared to ACE inhibitors (Egbuche et al, 2020).
They exert a similar physiological effect to ACE inhibitors, blocking the effect of angiotensin II at the angiotensin II receptor (type I) site, thus the downstream effects of angiotensin II on blood vessels and aldosterone biosynthesis is inhibited (Egbuche et al, 2020). They also have been shown extensively to improve both morbidity and mortality outcomes in heart failure patients (Granger et al, 2003). Due to significant risk of acute kidney injury, both ARBs and ACEIs should not be used in conjuction with one another.
Mineralocorticoid receptor antagonists (MRAs)
In severe HFrEF (EF <35%) or when symptoms are still not fully controlled in milder forms, then an MRA, also known as aldosterone antagonist, such as spironolactone or eplerenone, should be considered as add on therapy (British National Formulary, 2021). Contrastingly to other diuretic agents, such as furosemide or metolazone, MRAs do not deplete potassium and thus can be considered potassium-sparing. This is an advantage, particularly in patients with advanced HF who may be particularly susceptible to the pro-arrhythmic effects of hypokalaemia. On the other hand, when combined with other medications such as ACEI and ARBs, potassium levels and renal function should be closely monitored to avoid unchecked hyperkalaemia and renal dysfunction (Butler, 2010). Gynaecomastia is a side-effect that may occur in around 10% of patients treated with spironolactone (Egbuche et al, 2020); in these individuals' replacement with the more expensive eplerenone can be considered.
MRAs inhibit the activation of mineralocorticoid receptors via aldosterone, preventing the downstream action of aldosterone in the renal tubule, which would otherwise promote sodium reabsorption, increase fluid reabsorption, and exacerbate an already fluid overloaded system. Spironolactone acts as a weak diuretic through competitive antagonism of the aldosterone receptor. Combining aldosterone antagonists with optimal medical therapy (OMT) has been shown to improve morbidity and mortality in HF patients (Pitt et al, 2003).
Diuretics
Diuretics are recommended for symptomatic relief caused by fluid retention (Butler, 2010). These therapies work by increasing the amount of fluid excreted through the kidneys, thus promoting a more euvolemic state in patients that may otherwise be hypervolaemic as a consequence of left ventricular systolic dysfunction (LVSD).
Loop diuretics such as furosemide, bumetanide or torasemide are a mainstay of treatment for both acute and chronic HFrEF (Egbuche et al, 2020). Through action in the loop of Henle in the renal tubule, they promote natriuresis and diuresis. The less commonly used loop diuretics, bumetanide and torasemide, show better oral bioavailability compared to other agents, and thus may be used in patients whose diuresis is clinically refractory to furosemide (Egbuche et al, 2020).
Thiazide diuretics exert their effect in a different region of the nephron, more proximally than other classes, but ultimately promote sodium excretion (Egbuche et al, 2020). Thiazides and related diuretics exert their action by inhibiting sodium reabsorption at the beginning of the distal convoluted tubule. They can be used with loop diuretics in resistant oedema; however, their use has been observed to be dependent on adequate renal function, meaning that they are ineffective in patients with advanced chronic kidney disease. Metolazone (a thiazide-like diuretic) has a very potent effect and can be used at low doses combined with an oral loop diuretic in refractory HF even in patients with significantly reduced renal function (Rosenberg et al, 2005).
Other than MRAs, there is no evidence that diuretics reduce mortality in HF, only morbidity.
Specialist treatment
All these other agents should only be considered under the advice of a heart failure specialist in patients whose symptoms persist despite OMT.
Angiotensin II receptor-neprilysin inhibitors (ARNIs)
ARNIs are a newer class of medications. The flagship ARNI, Entresto, is a combination product, containing two active components: sacubitril (a neprilysin inhibitor) and valsartan (an ARB) (Electronic Medicines Compendium, 2020a). Patients on this treatment require careful monitoring of blood pressure and renal function. Recent studies have shown that, in specific HF populations, better mortality outcomes were shown with those taking ARNI, when compared with those taking ACEI (McMurray et al, 2014). Due to the potential risk of angioedema, the use of ARNIs is contraindicated with ACEIs and ARBs. Thus, patients should not be started on an ARNI within 36 hours of receiving a dose of an ACEI (Electronic Medicines Compendium, 2020a). Neprilysin is an endogenous enzyme, responsible for the breakdown of both natriuretic peptides and angiotensin II (Volpe et al, 2021). By inhibiting its action, levels of natriuretic peptides such as brain natriuretic peptide (BNP) can be increased, allowing for maximal antagonism of RAAS and natriuresis. It is important to consider that neprilysin inhibition alone, without angiotensin receptor blockade, would lead to a net increase in angiotensin II – hence sacubitril must be used in combination with an ARB to have a positive effect in heart failure patients (Volpe et al, 2021).
Ivabradine
Ivabradine, the only agent in its class, works through direct inhibition of the pacemaker current in the sinoatrial node to lower the resting heart rate (Egbuche et al, 2020). It has been shown in the SHIFT trial that the addition of ivabradine to the standard therapy led to a reduction in hospitalisation rates and improvement of mortality in patients with heart failure (with a resting heart rate of 70 beats per minute or greater) (Swedberg et al, 2010).
Digoxin
Digoxin is recommended as an add-on therapy for the presence of persistent symptoms despite the use of OMT, even in the presence of normal sinus rhythm. A trial carried out in 1997 found the use of digoxin resulted in significantly lower rates of hospitalisation in patients, however, there was no impact on mortality (He et al, 1997). The action of digoxin is via inhibition of sodium-potassium ATPase (Egbuche et al, 2020). Treatment results in an increase in intracellular sodium, which results in the reduction of the sodium concentration gradient that is necessary for the efflux of calcium (via the calcium/sodium exchanger) (Electronic Medicines Compendium, 2020b). The outcome is a mild positive inotropic effect via increased intracellular calcium (Egbuche et al, 2020). It must be noted, since digoxin has a narrow therapeutic index, careful monitoring of digoxin levels is required during initial stages of therapy, particularly in patients with co-morbidities and drug interactions. Beneficial effects of treatment are mostly seen in patients with serum digoxin concentrations of 0.8-2 nanogram/ml (EMC, 2020b).
Hydralazine in combination with a nitrate
Hydralazine, an arterial dilator, can be considered, combined with a nitrate, a venous dilator, for individuals who are intolerant to both ACE inhibitors and ARBs, as the combination has been shown in trials to improve patient survival (Cohn, 1988; British National Formulary, 2021). NICE guidelines (2018) recommend the treatment for individuals of African or Caribbean family origin who have moderate to severe HF. Using arterial and venous vasodilators in HF reduces both preload and after-load, thus off-loading the failing heart (Al-Mohammad, 2019).
Novel pharmacological therapies
Recently, large trials were carried out with the sodium-glucose cotransporter 2 (SGLT2) inhibitors, dapagliflozin (DAPA-HF trial) and empagliflozin (EMPEROR-reduced trial), both of which have shown positive outcomes in heart failure patients, regardless of the presence or absence of diabetes (McMurray et al, 2019; Packer et al, 2020). It lowers blood sugar by stopping the re-uptake of glucose in the kidney, therefore increasing excretion of glucose and sodium in the urine, a result of which leads to increased diuresis. The results of both of these studies demonstrated patients on the SLGT2 inhibitor treatments had a lower combined risk of cardiovascular death or hospitalisation and the treatments resulted in a slower progressive decline of renal function in patients with HFrEF.
Conclusion
The ultimate goal in pharmacological therapy of HF is reducing morbidity and mortality by targeting specific biochemical pathways; thus, slowing the fatal progression seen in patients with HF, as well as achieving effective symptomatic control. However, due to the presence of comorbidities and/or progressing disease, it must be noted the path to achieving guideline-based OMT with uptitration is often not straightforward and requires slow optimisation to take into account individual requirements and tolerability. This is one of the key roles of the specialist HF nurses in the community, who can work closely alongside hospital cardiologists, primary care practitioners and the patient and their families.
KEY POINTS:
- There is no evidence that diuretics (other than mineralocorticoid receptor antagonists) reduce mortality in heart failure with reduced ejection fraction (HFrEF) but they do improve symptoms in acute and chronic HF
- All patients, where possible, need starting on beta-blockers and ACE inhibitors soon after diagnosis of HFrEF and up-titrating
- COPD or asthma (unless brittle) is not a contraindication to beta-blockers nor is chronic kidney disease a contraindication to starting Angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs)
CPD reflective practice:
- Can you describe the basic pathophysiology of heart failure?
- How can comorbidities affect a patient's treatment for heart failure?
- When would you refer to a patient to a heart failure specialist?