Congestive Heart Failure

Incidence, pathophysiology and diagnosis

CHF is a common clinical condition which affects around 900,000 people in the United Kingdom. It is clinically defined as incapability of the heart to deliver blood and therefore, oxygen and nutrients at a rate which corresponds to the metabolic needs of body tissues. It is also a multifactorial syndrome which may result from any structural or functional cardiac or non-cardiac disorder.

The initial stage in the diagnosis of CHF involves a detailed history taking and physical examination accompanied by appropriate laboratory testings. Patients suspected of CHF are often presented with symptoms like breathlessness, fatigue, fluid retention and exercise intolerance. Moreover, patients may also experience symptoms like nocturia, anorexia and abdominal discomfort. However, none of these symptoms has sufficient sensitivity and specificity to confirm a diagnosis of CHF. Furthermore, laboratory testings like full blood count, renal, liver and thyroid function tests, urinanalysis, fasting lipids and glucose levels should be considered in all patients suspected of CHF to identify for other possible causes for those symptoms and factors that may aggravate CHF. Patients may also exhibit signs that are more specific for CHF such as raised jugular venous pressure, displaced apex beat, presence of a third heart sound and basal crepitations. Yet, further investigations are still needed as these signs only raise the clinical suspicion of CHF.

Subsequently, ECG recording or serum B-type natriuretic peptide (BNP) levels measurement should be performed in patients suspected of CHF since it is very unlikely for CHF patients with CHF to have a completely normal ECG and normal serum BNP levels. Yet, any abnormalities in either test cannot confirm a diagnosis of CHF and echocardiography is subsequently performed. Echocardiography is an important investigation which will confirm a diagnosis of CHF and may provide information on the underlying cause.

Drug pharmacology

Valsartan

Valsartan is an angiotensin II receptor blocker (ARB) which inhibits the action of angiotensin II by blocking angiotensin II type 1 (AT1) receptors via competitive antagonism, resulting in improved tissue perfusion, reduced vascular resistance and reduced cardiac afterload. The common adverse effects reported for valsartan are mild and it is also better tolerated than angiotensin-converting enzyme (ACE) inhibitors. Unlike ACE inhibitors, it is unlikely to produce persistent dry cough because it does not inhibit the breakdown of bradykinin. Moreover, it is less also likely than ACE inhibitors to cause angioedema since it does not inhibit the breakdown of prostaglandins. Thus, valsartan can be used as a substitute for ACE inhibitors in patients with CHF who are intolerant to ACE inhibitors due to persistent dry cough and angioedema. However, valsartan should be used with caution in patients with ACE inhibitor-related angioedema as cases of cross-reactivity have been reported.

Furosemide

Furosemide is a loop diuretic which is routinely used in CHF for relief of congestion symptoms such as breathlessness and fluid overload. It inhibits the Na/2Cl/K co-transporter in the think ascending limb of the loop of Henle to produce natriuresis and diuresis. The mechanisms by which furosemide exerts its vasodilator effects are not well understood but they are postulated to involve decreased vascular sensitivity to vasoconstrictors such as angiotensin II and noradrenaline, increased synthesis of vasodilating prostaglandins and decreased production of endogenous ouabain-like natriuretic hormone with vasoconstrictor effects. Furosemide has a relatively rapid onset and short duration of action. It is usually well absorbed from the gastrointestinal tract following oral administration. Yet, it is usually administered intravenously in CHF because there is reduced intestinal perfusion, resulting in impaired absorption. The common side effects reported for furosemide are mild gastrointestinal disturbances, hypotension, hyperuricaemia and electrolyte disturbances such as hyponatraemia and hypokalaemia. Hypokalaemia can predispose patients to arrhythmias as well as toxicity with other drugs. Unlike thiazide diuretics, furosemide is effective in patients with renal impairment although very large doses may be required in these patients. It is usually initiated at low doses which may subsequently be increased to produce adequate diuresis.

Carvedilol

Evidence for treatment of the condition

ARBs

The patient involved in this clinical case was prescribed with valsartan which is an ARB instead of an ACE inhibitor most likely because of intolerance the adverse effects of ACE inhibitors like persistent dry cough. ARBs are recommended for use as an alternative in patients with CHF who are intolerant to the adverse effects of ACE inhibitors as they have been demonstrated to be effective in reducing morbidity and mortality in these patients in numerous trials. Examples of ARBs that are licensed for used in the treatment of CHF are candesartan and valsartan.

The ELITE II study is a further randomised, double-blind controlled trial which was conducted to evaluate the influence of losartan and captopril on mortality in elderly patients with CHF. This study involved 3152 patients aged 60 years or older with NYHA class II-IV heart failure and LVEF of 40% or less. It was shown that losartan was better tolerated than captopril because there were significantly fewer patients in the losartan group who discontinued treatment with the study drug due to adverse effects (p < 0.001). Moreover, losartan also demonstrated similar efficacy with captopril in reducing mortality since there were no significant difference in the mortality rate between the two drugs (p = 0.06).

The CHARM-Alternative trial is another randomised, double-blind clinical trial which was conducted to evaluate the effectiveness of candesartan in the treatment of heart failure in 2,028 patients who are intolerant to ACE inhibitors. It was shown that the use of candesartan resulted in significantly fewer cardiovascular deaths in patients who are receiving candesartan when compared to placebo. Furthermore, the use of candesartan also resulted in significantly fewer hospitalisations due to heart failure (p < 0.0001) in these patients. Candesartan also appears to be well tolerated throughout the programme since both groups showed similar number of patients who discontinued treatment with the study drug. However, most treatment discontinuations were caused by the recurrence of ACE inhibitor-related adverse effects such as acute renal failure, hypokalaemia and hypotension. Thus, patients who are intolerant to ACE inhibitors due to these adverse effects require close monitoring of their renal function and blood pressure during treatment with candesartan since they are more susceptible to developing intolerance to ARBs.

In a further randomised, double-blind controlled trial was conducted by Maggioni et al. to evaluate the influence of valsartan on mortality and morbidity in 5,010 patients with CHF who are intolerant to ACE inhibitors due to adverse effects, the use of valsartan resulted in a relative risk reduction of 33% in morbidity as well as a relative risk reduction of 53% in mortality in patients in the valsartan group. Moreover, patients in the valsartan group also showed some improvements in LVEF, exercise performance and their quality of life.

A recent meta-analysis of data acquired from 17 relevant trials which involved 12,469 patients was conducted to evaluate the influence of ARBs on morbidity and mortality when used as a substitute or in addition to ACE inhibitors in the treatment of CHF. The use of ARBs showed similar efficacy with ACE inhibitors in reducing mortality (OR 0.96; 95% CI 0.75-1.23) and hospitalisations due to CHF (OR 0.86; 95% CI 0.69-1.06).

A similar outcome was observed in a further meta-analysis of data acquired from 24 relevant trials involving 38,080 patients which was conducted to evaluate the influence of ARBs on morbidity and mortality of patients with CHF and a high risk of acute myocardial infarction. It was shown that the use of ARBs led to a greater reduction in mortality and hospitalisations due to heart failure when compared to placebo. Moreover, ARBs also showed no significant difference with ACE inhibitors in reducing mortality and hospitalisations due to CHF.

Diuretics

Subsequently, the patient involved in this clinical scenario was prescribed with furosemide which is a loop diuretic since she showed congestion symptoms upon admission to the hospital. Diuretics have been a mainstay in the management of CHF since they have been shown to be effective in reducing morbidity and mortality in addition to providing symptom relief. Despite this, only limited evidences are available on the use of diuretics in the treatment of CHF.

A recent meta-analysis of data acquired from 18 randomised controlled trials which involved 928 patients was conducted to evaluate the effectiveness of diuretics in the treatment of CHF. It was demonstrated that the use of diuretics resulted in an absolute risk reduction of 8% in mortality in patients who received diuretics compared to placebo. In addition, a number needed to treat of 12 was also acquired from this meta-analysis indicating that only 12 patients have to be treated will diuretics in order to prevent one patient from death due to CHF. Furthermore, the use of diuretics resulted in significant improvement in exercise capacity (OR 0.37; 95% CI 0.10-0.64) when compared to other drugs that are used in the treatment of CHF such as ACE inhibitor and digoxin.

A multicentre, open-label trial was conducted in 170 patients aged 35 to 85 with NYHA class II-III heart failure to evaluate the safety and effectiveness of torasemide in the treatment of CHF in terms of incidence of adverse effects, improvement in NYHA class and symptom relief. Generally, the use of torasemide demonstrated a significant improvement in NYHA class (p < 0.001) and symptoms like breathlessness and paroxysmal nocturnal dyspnoea (p < 0.001). Moreover, peripheral oedema also resolved in 56 of 78 patients who were oedematous at the start of the trial (p < 0.001).

In a recent analysis of data acquired from the SOLVD study conducted by Cooper et al. to evaluate the influence of diuretics on arrhythmic mortality in patients with left ventricular dysfunction, the use of diuretics had resulted in a substantial increase in the risk of arrhythmia mortality (p < 0.001). Thus, potassium supplements are usually prescribed concurrently with diuretics like in this clinical case to avoid from hypokalaemia which will predispose the patient to arrhythmias and subsequently death.

β-blockers

β-blockers should be considered in patients with all NYHA classes of HF unless since they have been demonstrated to be effective in reducing morbidity and mortality associated with HF when used in combination with ACE inhibitors and diuretics in numerous controlled trials. Examples of β-blockers that are licensed for use in the treatment of CHF in the UK are carvedilol and bisoprolol. In addition, metoprolol is also another β-blocker which is routinely used in the treatment of CHF.

A randomised, double-blind controlled trial was conducted by Packer et al. to evaluate the influence of carvedilol on mortality in patients with severe CHF. This trial involved 2289 patients with NYHA class III-IV heart failure who were randomly assigned to receive carvedilol or placebo in addition to their existing treatment. It was demonstrated that the addition of carvedilol led to a 35% reduction in the risk of mortality as well as a 24% reduction in the risk of hospitalisations.

A comparable outcome was observed in a further randomised, double-blind controlled trial involving 3391 patients with NYHA class II-IV heart failure and LVEF of 40% or less was conducted to evaluate the influence of modified-released preparations of metoprolol on morbidity and mortality in patients with heart failure. It was demonstrated that the use of metoprolol resulted in a significant decrease in the risk of mortality and hospitalisations due to heart failure. There were also more patients in the metoprolol with improved NYHA class status and quality of life.

In a meta-analysis of data acquired from two large randomised clinical trial, namely CIBIS and CIBIS II which involved 3288 patients to evaluate the efficacy of bisoprolol in the treatment of CHF, the use of bisoprolol had resulted in a very substantial decrease in the risk of mortality (p < 0.001) along with hospitalisation due to CHF (p < 0.001). The outcome of this trial is comparable to those observed in previous trials conducted using carvedilol and metoprolol.

The COMET study is a randomised, double-blind controlled trial involving 1151 patients with NYHA class II-IV CHF and LVEF of 35% or less which was conducted to compare the efficacy of carvedilol, a non-selective β-blocker and metoprolol, a selective β1-blocker in the treatment of CHF. It was shown that the use of carvedilol resulted in a greater reduction in mortality and hospitalisations due to CHF compared to metoprolol. Both carvedilol and metoprolol also exhibited a similar safety profile as the number of patients who discontinued treatment with the study drug was similar for both drugs.

Conclusion

The use of ARBs as an alternative in patients who are intolerant to ACE inhibitors due to side effects seems to be promising since they showed similar efficacy with ACE inhibitors and they also appear to be better tolerated.

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