Diuretics

In chronic heart failure, diuretics are used to relieve pulmonary and peripheral oedema by increasing sodium and chloride excretion through blockade of sodium re-absorption in the renal tubule. Normally, in the proximal tubule, about 70% of sodium is reabsorbed along with water. In mild heart failure, either a thiazide or more often a loop diuretic is chosen depending on the severity of the symptoms experienced by the patient and the degree of diuresis required. Thiazides are described as ‘low-ceiling agents’ because maximum diuresis occurs at low doses, and they act mainly on the cortical diluting segment (the point of merger of the ascending limb with the distal renal tubule) at which 5–10% of sodium is normally removed. Although thiazides have some action at this site, they fail to produce a marked diuresis since a compensatory increase in sodium re-absorption occurs in the loop of Henle, and consequently thiazides are ineffective in patients with moderate-to-severe renal impairment (eGFR <30 mL/min) or persisting symptoms. Additionally, doses above the equivalent of bendroflumethiazide 5 mg have an increased risk of adverse metabolic effects with no additional symptomatic benefit. Thiazides are, therefore, now rarely used as sole diuretic therapy and are reserved for cases where the degree of fluid retention is very mild, renal function is not compromised or as an adjunct to loop diuretics (see below).

Loop diuretics are indicated in the majority of symptomatic patients and most patients will be prescribed one of either furosemide, bumetanide or torasemide in preference to a thiazide. These agents are known as ‘high-ceiling agents’ because their blockade of sodium re-absorption in the loop of Henle continues with increased dose. They have a shorter duration of action (average 4–6 h) compared to thiazides (average 12–24 h), and produce less hypokalaemia. In high doses, however, their intensity of action may produce hypovolaemia with risk of postural hypotension, worsening of symptoms and renal failure. In practice, high doses of furosemide (up to 500 mg/day) may be required to control oedema in patients with poor renal function. In the acute situation, doses of loop diuretics are titrated to produce a weight loss of 0.5–1 kg per day.

In longer term use, patients with heart failure frequently develop some resistance to the effects of loop diuretic due to a compensatory rebound in sodium retention. In this situation, a combination of thiazide and loop diuretics has been shown to have a synergistic effect, even in patients with reduced renal function. In the UK, metolazone is also used as an adjunct to augment the effects of loop diuretics. The potentially profound diuresis produced by such a combination poses serious risks, such as dehydration and hypotension, and patients who are prescribed metolazone in addition to an existing loop diuretic must be carefully monitored. In practice, patients with oedema treated with loop diuretics may best be treated using a degree of self-management. Some patients are instructed to make upward adjustment of loop diuretic dose or to add metolazone therapy on particular days, for example, when they self-record a gain of 2 kg or more in their body weight over a short period of time.

Diuretics also have a mild vasodilator effect that helps improve cardiac function and the intravenous use of loop diuretics reduces preload acutely by locally relieving pulmonary congestion before the onset of the diuretic effect. Effective diuretic therapy is demonstrated by normalisation of filling pressure. Therefore, continued elevation of the JVP suggests a need for more diuretic unless otherwise contraindicated. Intravenous furosemide must be administered at a rate not exceeding 4 mg/min to patients with renal failure, since it can cause ototoxicity when administered more rapidly.

Details of diuretic therapy used in left ventricular systolic dysfunction are summarised in Table 21.5.

ACE inhibitors

ACE inhibitors are indicated as first-line treatment for all grades of heart failure due to left ventricular systolic dysfunction, including those patients who are asymptomatic. These agents exert their effects by reducing both the preload and afterload on the heart, thereby increasing cardiac output.

ACE inhibitors act upon the renin–angiotensin–aldosterone system, and they reduce afterload by reducing the formation of angiotensin II, a potent vasoconstrictor in the arterial system. These drugs also have an indirect effect on sodium and water retention by inhibiting the release of aldosterone and vasopressin, thereby reducing venous congestion and preload. The increase in cardiac output leads to an improvement in renal perfusion, which further helps to alleviate oedema. ACE inhibitors also potentiate the vasodilator bradykinin and may intervene locally on ACE in cardiac and renal tissues.

ACE inhibitors are generally well tolerated by most patients and have been shown to improve the quality of life and survival in patients with mild-to-severe systolic dysfunction (CONSENSUS, 1987; CONSENSUS II, 1992; SOLVD-P, 1992; SOLVD-T, 1991; V-HeFT II, 1991), including those patients who have experienced a myocardial infarction (AIRE), 1993; SAVE, 1992; TRACE, 1995). When an ACE inhibitor is prescribed, it is important to ensure that the dose is started low and increased gradually, paying close attention to renal function and electrolyte balance. The dose should be titrated to achieve the target dose that has been associated with long-term benefits shown in clinical trials or (if not possible) the maximum tolerable dose. There is some evidence to suggest that high doses of ACE inhibitor are more effective than low doses in relation to reduction in mortality, although it is uncertain whether this is a general class effect (ATLAS, 1999). In clinical practice, it is possible that some patients may be treated with ACE inhibitors at doses below those used in clinical trials. As a consequence, actual outcomes in heart failure treatment may not be as good as expected from the trial findings.

The introduction of an ACE inhibitor may produce hypotension, which is most pronounced after the first dose and is sometimes severe. Patients at risk include those already on high doses of loop diuretics, where the diuretics cannot be stopped or reduced beforehand, and patients who may have a low-circulating fluid volume (due to dehydration) and an activated renin–angiotensin system. Hypotension can also occur where the ACE inhibitor has been initiated at too high a dose or where the dose has been increased too quickly after initiation. In the primary care setting, treatment must be started with a low dose which is usually administered at bedtime. In patients at particular risk of hypotension, a test dose of the shorter-acting agent captopril can be given to assess suitability for treatment before commencing long-term treatment with a preferred ACE inhibitor. Once it has been established that the ACE inhibitor can be initiated safely, the preferred option would be to switch to a longer acting agent with once- or twice-daily dosing, starting with a low dose which would be gradually titrated upwards to the recommended target (Table 21.6). Monitoring of fluid balance, blood biochemistry and blood pressure are essential safety checks during initiation and titration of ACE inhibitor therapy.

One of the most common adverse effects seen with ACE inhibitors is a dry cough and this is reported in at least 10% of patients. However, since a cough can occur naturally in patients with heart failure it is sometimes difficult to determine the true cause. ACE inhibitor therapy can also compromise renal function, although in patients in whom there is a reduction in renal perfusion due to worsening heart failure or hypovolaemia, renal dysfunction can also occur. Therefore, there are a number of instances where ACE inhibitor intolerance can be misdiagnosed in practice. Where ACE inhibitor intolerance is suspected, patients can usually be successfully rechallenged with an ACE inhibitor once their heart failure is more stable, although careful monitoring of the patient should be undertaken during initiation and subsequent dose titration. If the increase in the patient’s serum creatinine is >100% from baseline, the ACE inhibitor should be stopped, intolerance confirmed and specialist advice sought. Where the increase from baseline is 50–100%, the ACE inhibitor dose should be halved and serum creatinine concentration rechecked after 1–2 weeks. If renal function is stable and no cough or other adverse effects are reported, therapy should be continued. Where the problem persists, an alternative treatment option might be required, for example, ARB (similar benefits on morbidity and mortality, but there is a possibility of similar adverse effects on blood pressure and renal function) or hydralazine–nitrate combination.

ACE inhibitors are potentially hazardous in patients with pre-existing renal disease, as blockade of the renin-angiotensin system may lead to reversible deterioration of renal function. In particular, ACE inhibitors are contraindicated in patients with bilateral renal artery stenosis, in whom the renin-angiotensin system is highly activated to maintain renal perfusion. Since most ACE inhibitors or their active metabolites rely on elimination via the kidney, the risk of other forms of dose-related toxicity is also increased in the presence of renal failure. Fosinopril, which is partially excreted by metabolism, may be the preferred agent in patients with renal failure. ACE inhibitors are also contraindicated in patients with severe aortic stenosis because their use can result in a markedly reduced cardiac output due to decreased filling pressure within the left ventricle. Table 21.6 summarises the activity and use of ACE inhibitors.

Angiotensin II receptor blockers

Although comparisons of ACE inhibitors and ARBs have shown similar benefits on morbidity and heart failure mortality, only ACE inhibitors have been shown to have positive effects on all cause mortality. ARBs should, therefore, not be used instead of ACE inhibitors, unless the patient experiences intolerable side effects.

The use of ARBs as an adjunct to ACE inhibitor and β-blocker therapy has been associated with significant reductions in cardiovascular events and hospitalisation rate (CHARM Added, 2003). Although this finding is encouraging, the impact on mortality alone remains inconsistent and there is no clear consensus on when to use an ARB as adjunctive therapy. In studies involving patients unable to tolerate an ACE inhibitor, ARBs have been shown to be comparable to ACE inhibitors in reducing the risk of cardiovascular death and rate of hospitalisation, and in the control of symptoms in heart failure patients (CHARM Alternative, 2003; Val-HeFT, 2002). Therefore, ARBs are recommended for use as an alternative to ACE inhibitor therapy where intolerance has been confirmed. It is important to note that in patients who have renal failure secondary to ACE inhibitors, switching to an ARB is of no theoretical or practical benefit, as similar adverse effects are likely.

A recent meta-analysis has raised concerns about a possible increase of cancer in people taking ARBs (Sipahi et al., 2010). Although the implications of this are unclear it adds weight to the recommendation that ACE inhibitors, not ARBs, should be the first-line agent when selecting a drug to act on the renin-angiotensin system.

β-Blockers

Formerly, β-blockers have been contraindicated in patients with heart failure. However, the sympathetic neurohormonal overactivity that occurs in response to the failing heart has been identified as a decisive factor in the progression of ventricular dysfunction. Consequently, β-blockers have been tested in a number of clinical trials. There is now substantial evidence that β-blockers reduce mortality among patients with mild-to-moderate symptomatic heart failure (ANZ Carvedilol, 1997; CAPRICORN, 2001; CIBIS II, 1999; MERIT-HF, 1999; US Carvedilol, 1996) and those with severe heart failure (COPERNICUS, 2001). This beneficial effect also extends to the elderly heart failure population (SENIORS, 2005).

The use of β-blockers is, therefore, recommended for all patients with heart failure due to left ventricular systolic dysfunction, irrespective of age and the degree of dysfunction. However, due to their negative inotropic effects, β-blockers should only be initiated when the patient’s condition is stable. There is insufficient evidence for a class effect to be assumed illustrated by the fact that in one trial, metoprolol tartrate was found to be inferior to carvedilol (COMET, 2003). Currently, nebivolol, bisoprolol and carvedilol are the only licensed β-blockers for the treatment of heart failure in the UK.

It is likely that patients will experience a worsening of symptoms during initiation of therapy and, therefore, patients are started on very low doses of β-blocker (e.g. carvedilol 3.125 mg daily) with careful titration occurring over a number of weeks or months with careful monitoring. The goal is to titrate the dose towards those used in clinical trials that have been associated with morbidity and mortality benefits (carvedilol 25–50 mg daily). Table 21.6 summarises the activity and use of β-blockers in heart failure.

Despite the demonstrated benefits, there is ongoing concern that certain subgroups of patients with heart failure continue to be undertreated with β-blockers. These groups include patients with chronic obstructive pulmonary disease (COPD), peripheral vascular disease, diabetes mellitus, erectile dysfunction and older adults. With the exception of patients with reversible pulmonary disease, who have typically been excluded from β-blocker trials (CIBIS II, 1999; MERIT-HF, 1999), there is now sufficient evidence to justify the use of β-blockers licensed for heart failure in these patients. In addition, a systematic review of trials on cardio-selective β-blockers found no clinically significant adverse respiratory effects in patients with reversible COPD, although it would be prudent to use these agents in such patients with caution and with appropriate monitoring in place (Salpeter S. et al., 2005).

Aldosterone antagonists

The use of aldosterone antagonists as an adjunct to standard treatment has been shown to have an effect on morbidity and mortality in patients with heart failure. Spironolactone has been shown to reduce mortality and hospitalisation rates in patients with moderate-to-severe heart failure (RALES, 1999). The use of eplerenone has also been shown to be associated with similar benefits in early post-MI patients with symptomatic heart failure or early post-MI diabetic patients with asymptomatic heart failure (EPHESUS, 2003, EMPHASIS-HF, 2010).

Aldosterone can cause sodium and water retention, sympathetic activation and parasympathetic inhibition, all of which are associated with harmful effects in the patient with heart failure. Aldosterone antagonists counteract these effects by directly antagonising the activity of aldosterone, providing a more complete blockade of the renin–angiotensin–aldosterone system when used in conjunction with an ACE inhibitor. Although the combination of spironolactone (at a dose of 50 mg daily or more) and an ACE inhibitor is associated with an increased risk of developing hyperkalaemia, the use of a 25-mg daily dose has been shown to have little effect on serum potassium and provides a significant reduction in mortality. The use of spironolactone is, however, contraindicated in those patients with a serum potassium >5.5 mmol/L or serum creatinine >200 µmol/L. With eplerenone, similar contraindications exist and, therefore, close monitoring of blood biochemistry and renal function must be undertaken for use of either agent. The activity and use of spironolactone and eplerenone are summarised in Table 21.5.

Currently, there is no evidence available regarding the effectiveness and safety of combining an ACE inhibitor, ARB and an aldosterone antagonist, and therefore it is recommended that this combination is avoided until more information about this particular combination becomes available.

Digoxin

Although digoxin has an established role in the control of atrial fibrillation, its place in the treatment of heart failure is still the subject of debate. There is evidence to show that when digoxin has been used to treat heart failure in patients in sinus rhythm, as an adjunct to ACE inhibitor and diuretic therapy, then worsening of symptoms occurs on withdrawal of digoxin (PROVED, 1993; RADIANCE, 1993). While the use of digoxin in heart failure in patients in sinus rhythm has no measurable impact on mortality, it reduces the number of hospital admissions (DIG, 1997). Consequently, digoxin is currently recommended for use as add-on therapy at low doses in patients with moderate-to-severe heart failure who remain symptomatic despite adequate doses of ACE inhibitor, β-blocker and diuretic treatment. Due to the lack of effect on mortality, it is unlikely that digoxin would be considered before the other adjunctive therapies available.

Digoxin is a positive inotropic agent and acts by increasing the availability of calcium within the myocardial cell through an inhibition of sodium extrusion, thereby increasing sodium–calcium exchange and leading to enhanced contractility of cardiac muscle. Digoxin increases cardiac output in patients with co-existing atrial fibrillation by suppressing atrioventricular conduction and controlling the ventricular rate. In patients with atrial fibrillation, the serum digoxin concentration usually needs to be at the higher end of the reference range (0.8–2 µcg/L) or beyond to control the arrhythmia. However, a high serum digoxin concentration is not necessarily required to achieve an inotropic effect in patients in sinus rhythm. Digoxin is also associated with both vagal stimulation and a reduction in sympathetic nerve activity, and these may play important roles in the symptomatic benefits experienced by those patients in sinus rhythm receiving lower doses. In practice, the dose prescribed will be judged appropriate by the clinical response expressed as relief of symptoms and control of ventricular rate. Routine monitoring of serum digoxin concentrations in the pharmaceutical care of the patient is not recommended, other than to confirm or exclude digoxin toxicity or investigate issues around patient compliance.

Digoxin treatment is potentially hazardous due to its low therapeutic index and so all patients receiving this drug should be regularly reviewed to exclude clinical signs or symptoms of adverse effects. Digoxin may cause bradycardia and lead to potentially fatal cardiac arrhythmias. Other symptoms associated with digoxin toxicity include nausea, vomiting, confusion and visual disturbances. Digoxin toxicity is more pronounced in the presence of metabolic or electrolyte disturbances and in patients with cardiac ischaemia. Those patients who develop hypokalaemia, hypomagnesaemia, hypercalcaemia, alkalosis, hypothyroidism or hypoxia are at particular risk of toxicity. Treatment may be required to restore serum potassium, and in emergency situations intravenous digoxin-specific antibody fragments can be used to treat life-threatening digoxin toxicity. Table 21.7 summarises the activity and use of digoxin.

Table 21.7 Inotropic agents used in the treatment of heart failure

Nitrates/hydralazine

Nitrates exert their effects in heart failure predominantly on the venous system where they cause venodilation, thereby reducing the symptoms of pulmonary congestion. The preferred use of nitrates is in combination with an arterial vasodilator such as hydralazine, which reduces the afterload, to achieve a balanced effect on the venous and arterial circulation. The combined effects of these two drugs lead to an increase in cardiac output, and there is evidence to show the combination is effective and associated with a reduction in mortality in patients with heart failure (V-HeFT I, 1986). Although the combination can improve survival, the reduction in mortality is much smaller than that seen with ACE inhibitors (V-HeFT II, 1991), especially in the white population. The combination has been shown to reduce mortality, heart failure hospitalisation rates and quality of life in patients of African descent, when added as an adjunct to optimum medical therapy (A-HeFT, 2004) and this benefit is sustained (A-HeFT, 2007).

The evidence supports the use of hydralazine 300 mg daily with isosorbide dinitrate (ISDN) 160 mg daily (although in practice an equivalent dose of isosorbide mononitrate, ISMN, is often used). Since the emergence of ACE inhibitors, with their superior effects on morbidity and mortality, the combination has mainly been reserved for patients unable to tolerate, or with a contraindication to, ACE inhibitor therapy.

Organic nitrate vasodilators work by interacting with sulphydryl groups found in the vascular tissue. Nitric oxide is released from the nitrate compound and this in turn activates soluble guanylate cyclase in vascular smooth muscle, leading to the vasodilatory effect. Plasma nitric oxide concentrations are not clearly related to pharmacological effects because of their indirect action on the vasculature. Depletion of tissue sulphydryl groupings can occur during continued treatment with nitrates, and is partly responsible for the development of tolerance in patients with sustained exposure to high nitrate doses. Restoration of sulphydryl groupings occurs within hours of treatment being interrupted; therefore, nitrate tolerance can be prevented by the use of an asymmetrical dosing regimen to ensure that the patient experiences a daily nitrate-free period of more than 8 h.

In the acute setting, glyceryl trinitrate (GTN) is frequently administered intravenously, along with a loop diuretic, to patients with heart failure to relieve pulmonary congestion. When using this route of administration, it is important that a Teflon-coated catheter is used to avoid adsorption of the GTN onto the intravenous line.

ISDN can be given orally and is completely absorbed; however, only 25% of a given dose appears as ISDN in serum with 60% of an oral dose being rapidly converted to ISMN. ISMN is longer acting and, therefore, most of the accumulated effects of a dose of ISDN are attributable to the 5-isosorbide mononitrate metabolite. Consequently, a 20-mg dose of ISDN is approximately equivalent to a 10-mg dose of ISMN. In practice, nitrate preparations are usually given orally in the form of ISMN, and intravenously in the form of GTN (see Table 21.6).

Hydralazine has a direct action on arteriolar smooth muscle to produce arterial vasodilation. Its use is associated with the risk of causing drug-induced systemic lupus erythematosus (SLE). SLE is an uncommon multisystem connective tissue disorder that is more likely to occur in patients classified as slow acetylators of hydralazine, which accounts for almost half the UK population.

Inotropic agents

The use of inotropic agents (except digoxin) is almost exclusively limited to hospital practice, where acute heart failure may require the use of one or more inotropic agents, particularly the sympathomimetic agents dobutamine and dopamine, in an intravenous continuous infusion. These agents have inotrope-vasodilator effects which differ according to their action on α, β₁, β₂ and dopamine receptors (β₁-agonists increase cardiac contractility, β₂-agonists produce arterial vasodilation, dopamine agonists enhance renal perfusion). With dopamine, low doses (0–2 µcg/kg/min) have a predominant effect on dopamine receptors within the kidneys to improve urine output, intermediate doses (2–5 µcg/kg/min) affect β₁-receptors, producing an inotropic effect, and high doses (10 µcg/kg/min) have a predominant action on α-adrenoreceptors. Dobutamine has a predominantly inotropic and vasodilator action due to the action of the (+) isomer selectively on β-adrenoreceptors (see Table 21.7). Tolerance to sympathomimetic inotropic agents may develop on prolonged administration, particularly in patients with underlying ischaemia, and is also associated with a risk of precipitating arrhythmias.

Noradrenaline (norepinephrine) is an α-adrenoreceptor agonist where its vasoconstrictor action limits its usefulness in severely hypotensive patients such as those in septic shock. Adrenaline (epinephrine) has β₁, β₂ and α-adrenoreceptor agonist effects and is used in patients with low vascular resistance. However, it is more arrhythmogenic than dobutamine and should be used with caution.

Phosphodiesterase inhibitors are rarely used in clinical practice as a consequence of trials showing an increased risk of mortality (PROMISE, 1991).

Other agents

Direct-acting vasodilators such as sodium nitroprusside are rarely used except in the acute setting when they are given by continuous infusion. Vasodilation occurs as a result of the catalysis of nitroprusside in vascular smooth muscle cells to produce nitric oxide. The fact that nitric oxide production in this instance is via a different route when compared to the catalysis of GTN (where there is a need for sulphydryl groups) may explain why there is little tolerance seen with nitroprusside. In patients with impaired renal function thiocyanate, a metabolic product of nitroprusside can accumulate over several days, causing nausea, anorexia, fatigue and psychosis.

Patients with coronary heart disease may be candidates for calcium-blocking antianginal vasodilators. However, some of these agents can exacerbate co-existing heart failure, since their negative inotropic effects offset the potentially beneficial arterial vasodilation. Amlodipine and felodipine have a more selective action on vascular tissue and, therefore, a less pronounced effect on cardiac contractility than other calcium antagonists and should be the agents of choice where appropriate.

In hospitalised patients in whom compromised respiratory function remains despite medical management of heart failure, the treatment options include mechanical ventilation, continuous positive airway pressure ventilation and the use of intra-aortic balloon pumping.

Guidelines

Several groups have produced evidence-based consensus clinical guidelines for the management of chronic heart failure. The focus of the various guidelines tends to be on chronic medication use (National Institute for Health and Clinical Excellence, 2010; American College of Cardiology/American Heart Association Task Force on Practice Guidelines, 2009; European Society of Cardiology, 2008; Scottish Intercollegiate Guidelines Network, 2007). All guidelines confirm that ACE inhibitors and β-blockers should be given to all patients with all grades of heart failure, whether symptomatic or asymptomatic, in the absence of contraindication or intolerance.

In ACE inhibitor-intolerant patients, the preferred alternative is an ARB. However, it should be remembered that where ACE inhibitor intolerance is due to renal dysfunction, hypotension or hyperkalaemia, similar effects could be expected with an ARB. If an ARB is an unsuitable alternative, the use of hydralazine/nitrate combination or digoxin could be considered, although the latter combination of agents has no effect on mortality. For patients with symptomatic heart failure, a loop diuretic is usually recommended to treat oedema and control symptoms. In heart failure patients who are still symptomatic despite being on optimum therapy (ACE inhibitor, β-blocker with/without a diuretic), the use of adjunctive therapies is recommended which can include ARB, aldosterone antagonists, hydralazine/nitrate combination and digoxin where the patient is still in sinus rhythm.

There is also debate as to whether diastolic dysfunction is a true diagnosis. The cause of ‘apparent’ heart failure symptoms can in many cases be attributed to another disease/condition such as respiratory disease, obesity or ischaemic heart disease. However, there may also be some patients in whom the cause of heart failure symptoms remains uncertain. Therefore, specific recommendations for the drug treatment of diastolic heart failure are still lacking.

Patient education and self-monitoring

The patient must be in a position to understand the need for treatment and the benefits and risks offered by prescribed medication before concordance with a treatment plan can be reached. Appropriate patient education is necessary to encourage an understanding of their condition, inform patients of the extent of their condition and how prescribed drug treatment will work and affect their daily lives. It is also important to encourage them to be an active participant in their care where appropriate. Specific advice should be given to reinforce the timing of doses and how each medication should be taken. Patients also need to be advised of potentially troublesome symptoms that may occur with the medication, and whether such effects are avoidable, self-limiting or a cause for concern.

Patients should be made aware that diuretics will increase urine production, and that doses are usually timed for the morning to avoid inconvenience during the rest of the day or overnight. However, there are cases where patients are advised that they can alter the timing of the dose(s) if required to suit their lifestyle or social commitments, with the agreement of their doctor. There are also some patients who use a flexible diuretic dosing regimen, where they can take an extra dose of diuretic in response to worsening signs or symptoms as part of an agreed self-management protocol. To use such a regimen, the patient has to monitor and record their weight on a daily basis, and have clear instructions to take an extra dose of diuretic when a notable increase in weight is detected as a result of fluid retention, and when to seek medical attention. It is also important for patients to be aware of signs and symptoms of drug toxicity with medicines such as digoxin, for example anorexia, diarrhoea, nausea and vomiting, and be aware of the action to be taken should these symptoms occur.

Timing of doses is also important. If a nitrate regimen is being used, then patients must be made aware that the last dose of the nitrate should be taken mid to late afternoon to ensure that a nitrate-free period occurs overnight, thus, reducing the risk of nitrate tolerance. However, patients with prominent nocturnal symptoms require separate consideration. Where β-blockers are introduced, it is important that the patient is aware of the need for gradual dose titration due to the risk of the medication aggravating heart failure symptoms. Certain medicines for the treatment of minor ailments that are available for purchase over the counter without a prescription can aggravate heart failure, such as ibuprofen, antihistamines and effervescent formulations. It is important that patients know what action to take if their symptoms become progressively worse, and whom to contact when necessary for advice. Table 21.8 provides a general patient education and self-monitoring checklist, highlighting the typical areas where advice should be given.

Table 21.8 Patient education and self-monitoring in the treatment of heart failure

Potential problems with diuretic therapy

The use of diuretic therapy for sodium and water retention is common in the treatment of heart failure, although there can be a number of problems for the patient to contend with. Elderly patients in particular are at risk from the unwanted effects of diuretics. The increase in urine volume can worsen incontinence or precipitate urinary retention in the presence of an enlarged prostate, while overuse can lead to a loss of control of heart failure and worsening of symptoms. Rapid diuresis with a loop diuretic leading to more than a 1-kg loss in body weight per day may exacerbate heart failure due to an acute reduction in blood volume, hypotension and diminished renal perfusion, with a consequent increase in renin release. Prolonged and excessive doses of diuretics can also contribute to symptoms of fatigue as a consequence of electrolyte disturbance and dehydration. The adverse biochemical effects of excessive diuresis include uraemia, hypokalaemia and alkalosis. Diuretic-induced glucose intolerance may affect diabetic control in type 2 diabetes, but more commonly diuretics reveal glucose intolerance in patients who are not diagnosed as being diabetic. Diuretics also increase serum urate leading to hyperuricaemia, although this may not require a change in drug therapy if symptoms of gout are absent (estimated incidence of 2%).

Hyponatraemia may occur with diuretics, and is usually due to water retention rather than sodium loss. Severe hyponatraemia (serum sodium concentration of less than 115 mmol/L) causes confusion and drowsiness. It commonly arises when potassium-sparing agents are used in diuretic combinations.

Diuretics may also lead to hypokalaemia as a result of urinary sodium increasing the rate of K⁺/Na⁺ exchange in the distal tubule. Serum potassium concentrations below 3.0 mmol/L occur in less than 5% of patients receiving diuretics. The occurrence of hypokalaemia is hazardous for patients receiving digoxin and also for those with ischaemic heart disease or conduction disorders. It is more commonly found with thiazide diuretics than loop agents, and is more likely to occur when diuretics are used for heart failure than for hypertension. This is probably due to the fact that higher doses are used and there is an associated activation of the renin–angiotensin system. Patients with a serum potassium level of less than 3.5 mmol/L require treatment with potassium supplements or the addition of a potassium-sparing diuretic. The use of a potassium-sparing diuretic is considered to be more effective at preventing hypokalaemia than using potassium supplements. Prevention of hypokalaemia requires at least 25 mmol of potassium, while treatment requires 60–120 mmol of potassium daily. Since proprietary diuretic-potassium combination products usually contain less than 12 mmol in each dose, their use is often inappropriate.

Potassium supplements are poorly tolerated at the high doses often needed to treat hypokalaemia, and a liquid formulation is more preferable to a solid form. This is mainly due to the fact that solid forms can produce local high concentrations of potassium salts in the gastro-intestinal tract, with the risk of damage to the tract in patients with swallowing difficulties or delayed gastro-intestinal transit. In patients with deteriorating renal function or renal failure, the use of potassium supplements or potassium-sparing diuretics might cause hyperkalaemia, and therefore careful monitoring of these agents is essential.

Potential problems with ACE inhibitor and ARB therapy

ACE inhibitors are the cornerstone of the treatment of heart failure, but there are also risks associated with their use. ARBs, which also act on the renin–angiotensin–aldosterone system, pose similar risks to those recognised for ACE inhibitors. Both agents can predispose patients to hyperkalaemia through a reduction in circulating aldosterone; therefore, potassium supplements or potassium-retaining agents should be used with care when co-prescribed, and careful monitoring of serum potassium should be mandatory. Although potassium retention can be a problem with ACE inhibitors and ARBs, it can also be an advantage by helping to counteract the potassium loss that can result from the use of diuretic therapy. However, since this effect on potassium cannot be predicted, laboratory monitoring is still necessary to confirm that serum potassium concentration remains within safe limits.

The use of an aldosterone antagonist as adjunctive therapy with an ACE inhibitor (or ARB if the patient is ACE inhibitor intolerant) can be safely undertaken with minimal effects on the serum potassium concentration, provided that recommended target doses for the aldosterone antagonist are not exceeded (see Table 21.5). Although this is usually the case, laboratory monitoring of potassium is mandatory to ensure patient safety. Heparin therapy has also been shown to increase the risk of hyperkalaemia when used alongside ACE inhibitor or ARB therapy, and therefore a similar approach to monitoring should be taken when co-prescribed.

When initiating ACE inhibitor or ARB therapy, volume depletion due to prior use of a diuretic increases the risk of a large drop in blood pressure occurring following the first dose. As a consequence, diuretic treatment is usually withheld during the initiation phase of therapy in an effort to minimise this effect.

A dry cough, which may be accompanied by a voice change, occurs in about 10% of patients receiving an ACE inhibitor. It is more common in women and is associated with a raised level of kinins. Rashes, loss or disturbances of taste, mouth ulcers and proteinuria may also occur with ACE inhibitor therapy, particularly with captopril. These unwanted effects tend to be more common in patients with connective tissue disorders.

A number of ACE inhibitors are administered as pro-drugs, so close monitoring is advised in patients with liver dysfunction, as this could reduce the benefits associated with their use. Most ACE inhibitors are dependent on the kidney for excretion, and require careful dosage titration in patients with existing renal dysfunction. Differences in the pharmacokinetic characteristics do not fully explain the differences in duration of action seen with the ACE inhibitors, as this is also related to ACE binding affinity. Throughout treatment the dose must be individualised to obtain maximum benefit in relation to symptom relief and survival, with minimum side effects. When the experience of adverse effects requires a review of therapeutic alternatives, ARBs can be considered as an alternative treatment option. Although the side effect profile of ARB therapy is very similar to that of ACE inhibitors, it is not identical.

Potential problems with β-blocker therapy

Until recently, the use of β-blockers was contraindicated in patients with heart failure due to negative inotropic and chronotropic effects. However, β-blockers have clearly been shown to be safe and effective in patients with heart failure and should be used in all patients in the absence of contraindications or intolerance. Initiation of treatment and titration of dose must be done under close supervision, with very small dose increments used to minimise transient worsening of heart failure symptoms. Titration of the dose to target is normally performed over a number of weeks or months, and close patient monitoring is required to ensure safety is not compromised. The maximum tolerable dose for a patient may be below the target dose and may limit further dose titration. Monitoring for excessive bradycardia or rapid deterioration of symptoms is necessary to ensure patient safety, while also monitoring the patient’s prescribed dose to ensure that dosage increments are gradual and the patient is not subjected to an overall worsening of symptoms.

Potential problems with digoxin therapy

Although digoxin has been shown to reduce hospitalisation rates for patients with heart failure, its use is associated with a range of adverse effects including non-specific signs and symptoms of toxicity such as nausea, anorexia, tiredness, weakness, diarrhoea, confusion and visual disturbances. Digoxin also has the potential to cause fatal arrhythmias. It slows atrioventricular conduction and produces bradycardia, but it may also cause various ventricular and supraventricular arrhythmias. Digoxin toxicity typically causes conduction disturbances with enhanced automaticity leading to premature ventricular contractions. Patients at particular risk are those with myocardial ischaemia, hypoxia, acidosis or renal failure.

The appropriateness of digoxin dosage should be guided by assessment of the patient’s renal function (from serum creatinine and creatinine clearance determinations) and from the patient’s pulse rate. Renal function may also be affected by drug therapy or loss of control of heart failure; therefore, any medicine which affects in digoxin clearance will have an impact on the serum digoxin concentration. The possibility of a high serum digoxin concentration should also be considered in any patient whose health deteriorates or who shows signs and symptoms of potential digoxin toxicity.

Potential problems with other cardiovascular drugs

There are a number of other cardiovascular drugs that may be prescribed for patients with diseases or conditions other than heart failure, with some agents capable of worsening or aggravating symptoms. Patients with coronary artery disease may be candidates for calcium-blocking antianginal vasodilators. However, some of these agents, for example, diltiazem and verapamil, can exacerbate co-existing heart failure, since their negative inotropic effects offset the potentially beneficial arterial vasodilation. Second-generation dihydropyridines such as amlodipine and felodipine have a preferential action on the vasculature. They have less pronounced effects on cardiac contractility than other calcium antagonists, and this makes them the agents of choice where a limitation of the heart rate is not required.

Symptoms of fainting or dizziness on standing may indicate a need to review diuretic or vasodilator therapy. Patients should be reassured about mild postural effects and given advice to avoid standing from their chair too quickly. The patient and the health care team need to confirm the safety of the patient’s treatment plan regularly, and be vigilant for any signs or symptoms suggesting otherwise.

A summary of monitoring activity required to ensure the safety of drug use is outlined in Table 21.12.

Table 21.12 Monitoring the safety of drug treatment in patients with heart failure

Potential problems with non-cardiovascular agents

A number of agents should be avoided or used with caution in patients with heart failure because of their known negative inotropic or pro-arrhythmic effects that may aggravate symptoms of heart failure (see Box 21.1). In particular, the use of non-steroidal anti-inflammatory drugs (NSAIDs) should be actively discouraged where possible. Not only do NSAIDs cause fluid retention and put patients at increased risk of bleeding, especially if they are already taking antiplatelets or anticoagulants, there is also an increased risk of acute renal failure, particularly in those on long-term use and in the elderly. Recent articles have described the synergistic/cumulative adverse renal effects of combinations of ACE inhibitors or ARBs with diuretics and NSAIDs, which are particularly common in patients with heart failure.