The patient involved in this clinical case is LC, a 72 year-old Chinese female. She weighs 50kg and is 1.58m tall. She is a widow with eight children. The patient has no history of alcohol intake or smoking. She also has no known relevant family history and drug allergy.
History of presenting complaint
The patient was presented with bilateral lower leg swelling and progressively worsening shortness of breath (SOB) over the past two months. She also has nausea, paroxysmal nocturnal dyspnoea (PND) and inability to tolerate orally on admission.
Past medical history
The patient was diagnosed with chronic rheumatic heart disease with mitral stenosis and tricuspid regurgitation when she was admitted for her first episode of chronic heart failure (CHF) last year. She was also diagnosed with atrial fibrillation (AF) since 10 years ago for which she was admitted again on a separate occasion last year for spontaneous bleeding over buccal mucosa secondary to overwarfarinisation.
Prior to admission, she was on furosemide 40mg BD, valsartan 80mg BD and carvedilol 25mg BD for her CHF. Besides that, she was on warfarin 1mg daily and amiodarone 200mg OD for her AF. She was also on trimetazidine 35mg BD for her ischaemic heart disease and multivitamin supplement one tablet OD. In addition, she was prescribed with potassium chloride 600mg BD to replace the potassium lost due to furosemide.
On examination, she was alert and conscious and was able to speak in full sentences. The patient also showed bilateral pitting oedema up to the knees. Her vital signs were normal. She was afebrile. Her blood pressure was 150/70mmHg, her heart rate was 80 beats per minute and her oxygen saturation (SpO2) was 98%. There were bibasal creps in both lungs. Her abdomen was tender on palpation. Cardiovascular examination revealed displacement of apex beat to the 6th intercostal space and a presystolic murmur was heard at the apex.
Investigations that were performed on the patient include electrocardiogram (ECG) which showed atrial flutter but no acute ischaemic changes, full blood count (FBC), renal and liver function tests, chest x-ray and urinalysis. Her prothrombin time (PT), activated partial thromboplastin time (APTT), INR and troponin I levels were also measured.
Some of her FBC parameters were lower than their respective reference range. Her red blood cell count was 3.28 ×1012/L (reference range 3.8-4.8 ×1012/L), her haemoglobin count was 9.6g/dL (reference range 12 - 15 g/dL), her haematocrit count was 0.28L/L (reference range 0.36-0.46L/L) and her platelets count was 139 × 109/L (reference range 150 - 400 × 109/L). On the other hand, her PT, APTT and INR results were higher than their respective reference range. Her PT was 32.8 seconds (reference range 11.8-13.7 seconds), her APTT was 62 seconds (reference range 22.5-37.5 seconds) and her INR was 3.48 (reference range 2-3).
Her plasma sodium was 129mmol/L (reference range 136-146mmol/L) and her plasma chloride was 95mmol/L (reference range 98 - 107mmol/L). Both of these values were lower than their respective reference range. Her plasma creatinine was 132µmol/L (reference range 58 - 96µmol/L) and was substantially higher than the reference range. Her plasma potassium was 3.5mmol/L (reference range 3.5 - 5.1mmol/L) and was within the reference range.
Both her plasma aspartate transaminase (AST) and alanine transferase (ALT) were normal since they were only slightly higher than their respective reference range. Her plasma AST was 35IU/L (reference range < 31IU/L) and her plasma ALT was 44IU/L (reference range < 34IU/L).
The patient was diagnosed with acute CHF secondary to non-compliance to fluid restriction.
The patient was started on oxygen therapy at a flow rate of 3L per minute. She was also prescribed with IV furosemide 60mg BD. Some of her previous medications were continued which include tablet trimetazidine 35mg BD, tablet amiodarone 200mg OD, tablet valsartan 80mg BD and tablet carvedilol 25mg BD. Her input and output chart was monitored strictly and her fluid intake was restricted to 1L per day. Besides that, she was propped up and her SpO2 was monitored every 6 hourly.
On the night of day 1, she was alert and conscious and was able to speak in full sentences. She was mildly tachypnoeic and her leg swelling worsened. On examination, she showed pitting oedema up to the knees but no sacral oedema. Her vital signs were normal. She was afebrile. Her blood pressure was 150/90mmHg and her heart rate was 80 beats per minute. On cardiovascular examination, a presystolic murmur was heard at the apex. There were still bibasal creps in both lungs. She was prescribed with tablet slow potassium 1.2g BD because her plasma potassium levels are at the lower end of the reference range. Her serum urea and electrolytes test was reviewed so that her furosemide dose could be adjusted to prevent from overdiuresis.
On day 2, her leg swelling decreased but she was still having mild SOB. There were minimal bibasal creps in both lungs. She was also suspected to have acute renal failure because her latest plasma creatinine was increased to 180mmol/L from her baseline plasma creatinine of 96mmol/L. Her blood pressure was 90/50 mmHg, her heart rate was 82 beats per minute and her INR was 3.42. Subsequently, her IV furosemide dose was decreased from 60mg BD to 40mg BD. Her tablet slow potassium dose was decreased from 1.2g BD to 600mg BD due to an increase in plasma potassium to 4.1mmol/L. Moreover, her fluid intake was restricted to 1 L per day and her INR measurement was to be repeated. Valsartan was withheld because she was suspected of acute renal failure while warfarin was withheld because her INR was 3.42 and was higher than the reference range.
On day 3, her leg swelling had resolved but she was still having mild SOB. Her input was 900mL and her output was 700mL. Her blood pressure is 95/58mmHg, her heart rate was 98 beats per minute and her SpO2 was 99%. Subsequently, her INR measurement was repeated and she was restarted on tablet warfarin 1mg OD. Moreover, her IV furosemide 40mg BD was to be stopped and tablet furosemide was started at a dose of 40mg BD. Her tablet slow potassium dose was also increased from 600mg BD to 1.2g BD. Her fluid intake was maintained at 1L per day. Furthermore, her BP was monitored closely and her renal function was monitored daily.
CHF is a common clinical condition which affects around 900,000 people in the United Kingdom (UK). The prevalence of CHF increases with age and the mean age at the time of diagnosis is 76 years old. It is also more common in men than in women of all age groups.1
CCF 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.2, 3 It is also a multifactorial syndrome which may result from any non-cardiac or cardiac disorder that impairs the ability of the heart to relax and contract properly.1, 2 This will subsequently lead to the activation of several compensatory mechanisms that are responsible for maintaining cardiac output and mean arterial pressure in CHF.4
Following activation of the sympathetic nervous system in CHF, the heart will be exposed to higher levels of catecholamines resulting in tachycardia and increased cardiac output. Higher levels of renin are also released in CHF in response to decreased renal perfusion resulting in increased production of angiotensin II, which is a potent vasoconstrictor and aldosterone release. Subsequently, the aldosterone released will cause sodium and water restriction resulting in an expanded blood volume and increased preload.3, 4 These mechanisms are also responsible for some of the symptoms of CHF and may contribute to disease progression in the later stages of CHF.4
The initial stage in the diagnosis of CHF involves a detailed history taking and physical examination accompanied by appropriate laboratory testing.3 Patients suspected of CHF are often presented with symptoms like breathlessness, fatigue, fluid retention and exercise intolerance.1, 2 They may also experience symptoms like nocturia, anorexia and abdominal discomfort.1 However, none of these symptoms has sufficient sensitivity and specificity to confirm a diagnosis of CHF.2 Furthermore, laboratory testing like FBC, renal, liver and thyroid function tests, urinanalysis, fasting lipids and glucose levels should be considered in all patients suspected of CHF to identify other possible causes for those symptoms and factors that may aggravate CHF.1 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.1, 2 Yet, further investigations are still needed as these signs only raise the clinical suspicion of CHF.2
Subsequently, ECG recording or serum B-type natriuretic peptide (BNP) levels measurement should be performed in patients suspected of CHF because it is very unlikely for patients with CHF to have a completely normal ECG and normal serum BNP levels. However, any abnormalities in either test cannot confirm a diagnosis of CHF. Echocardiography is an important investigation which will confirm a diagnosis of CHF and may provide information on the underlying cause.1, 2, 5 The New York Heart Association (NYHA) classification can then be used to assess the severity of CHF.1, 2
Table 1: NYHA classification1, 2, 4
No limitation in regular physical activity
Mild limitation in regular physical activity
Marked limitation in regular physical activity
Unable to perform any physical activity without discomfort
Pharmacological basis for drug therapy
Valsartan is an angiotensin II receptor blocker (ARB) which inhibits the action of angiotensin II by blocking angiotensin II type 1 (AT1) receptors through competitive antagonism, resulting in improved tissue perfusion, reduced vascular resistance and reduced cardiac afterload.6, 7 Like ACE inhibitors, valsartan may also cause hypotension, reversible renal impairment and hyperkalaemia.1, 8 The common adverse effects of valsartan are relatively mild and include dizziness, diarrhoea, taste disturbance and fatigue.7, 8 Unlike ACE inhibitors, it is unlikely to produce persistent dry cough because it does not inhibit the breakdown of bradykinin.4, 8 Moreover, it is less also likely than ACE inhibitors to cause angioedema since it does not inhibit the breakdown of prostaglandins.7 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.7, 8 However, valsartan should be used with caution in patients with ACE inhibitor-related angioedema as cases of cross-reactivity have been reported.4
Furosemide is a loop diuretic which is routinely used in CHF for relief of congestion symptoms like breathlessness and fluid overload.1, 2 It inhibits the Na/2Cl/K co-transporter in the think ascending limb of the loop of Henle to produce natriuresis and diuresis.6 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 prostaglandins as well as decreased production of endogenous ouabain-like natriuretic hormone with vasoconstrictor effects.4, 6 The common adverse effects of furosemide are mild gastrointestinal disturbances, hypotension, hyperuricaemia as well as electrolyte disturbances such as hyponatraemia and hypokalaemia.8 Hypokalaemia can predispose patients to arrhythmias as well as toxicity with other drugs.6, 9 Unlike thiazide diuretics, furosemide is effective in patients with renal impairment although extremely large doses may be required in these patients.4, 8 It is often initiated at low doses which may be increased to produce adequate diuresis.1
Carvedilol is a non-selective β-blocker which is often used in patients with stable mild to moderate CHF in addition to their existing treatment with ACE inhibitors and diuretics.1, 2 It acts by reducing the harmful effects associated with sympathetic overactivity and also the release of renin in CHF. It also acts on α1-receptor to inhibit arterial constriction resulting in reduced cardiac output. Carvedilol inhibits the direct effect of catecholamines on the heart. Moreover, it also acts on β1-receptors to reduce structural and physiological changes of the heart.10 The additional antioxidant effect of carvedilol may also contribute to its beneficial effects in the treatment of CHF.11 The common adverse effects of carvedilol are postural hypotension, dizziness, gastrointestinal disturbances, fatigue and bradycardia.8 It is often initiated at a low doses which may be increased in the later course of the treatment to prevent from worsening of CHF due to its negative inotropic effects.4
Evidence for treatment of the condition
The patient involved in this clinical case was prescribed with valsartan, which is an ARB instead of an ACE inhibitor most likely due to intolerance to 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 decreasing morbidity and mortality in these patients in numerous trials. Examples of ARBs that are used in the treatment of CHF include losartan, candesartan and valsartan.1, 8
In a randomised, double-blind controlled trial which 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, the use of valsartan led to a relative risk reduction of 33% in mortality as well as a relative risk reduction of 53% in hospitalisations due to CHF in patients who are receiving valsartan.12 Valsartan also showed comparable efficacy with enalapril, which is an ACE inhibitor in decreasing mortality because a similar outcome was observed in the CONSENSUS trial which was conducted to evaluate the influence of enalapril on mortality in 253 patients with NYHA class IV CHF, in which the use of enalapril led to a relative risk reduction of 27% in mortality.12, 13 Furthermore, patients who are receiving valsartan also showed improvements in left ventricular ejection fraction (LVEF), exercise performance and quality of life. The use of valsartan also led to a reduction in serum BNP levels and norepinephrine release.12
The CHARM-Alternative trial is a further randomised, double-blind clinical trial which was conducted to evaluate the efficiency of candesartan in the treatment of CHF in 2,028 patients with symptomatic CHF and LVEF of 40% or less who are intolerant to ACE inhibitors. It was demonstrated that the use of candesartan resulted in significantly less cardiovascular deaths (p < 0.001) and hospitalisations due to CHF (p < 0.0001) compared to placebo. It also appears to be well tolerated throughout the trial since both groups showed similar number of patients who discontinued treatment with the study drug. However, it was noted that most treatment discontinuations were caused by the recurrence of ACE inhibitor-related adverse effects such as acute renal failure, hypokalaemia and hypotension in patients with previous intolerance.14
The ELITE II losartan heart failure survival study is also a randomised, double-blind controlled trial which was conducted to compare the efficiency of losartan and captopril in decreasing mortality in 3,152 elderly patients with NYHA class II-IV CHF and LVEF of 40% or less. It was demonstrated that losartan was better tolerated compared to captopril since there were significantly less patients who were receiving losartan discontinued treatment with the study drug due to intolerance to adverse effects (p < 0.001). Losartan also showed comparable efficiency with captopril in decreasing mortality since there were no significant difference in the all-cause mortality rate between the two drugs (p = 0.06).15
A recent meta-analysis of data from 17 randomised controlled trials which involved 12,469 patients was conducted by Jong et al. 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 demonstrated comparable efficacy with ACE inhibitors in decreasing mortality (OR 0.96; 95% CI 0.75-1.23) and hospitalisations due to CHF (OR 0.86; 95% CI 0.69-1.06).16
A comparable outcome was observed in a further meta-analysis of data from 24 randomised controlled trials which was conducted to evaluate the influence of ARBs on morbidity and mortality in 38,080 patients with CHF as well as high-risk acute myocardial infarction. It was demonstrated that the use of ARBs led to greater reduction in all-cause mortality (OR 0.83; 95% CI 0.69-1.00) and hospitalisations due to CHF (OR 0.64; 95% CI 0.53-0.78) compared to placebo. Moreover, ARBs also showed similar efficacy with ACE inhibitors in decreasing all-cause mortality (OR 1.06; 95% CI 0.90-1.26) and hospitalisations due to CHF (OR 0.95; 95% CI 0.80-1.13).17
The patient involved in this clinical case was also prescribed with furosemide, which is a loop diuretic because she had bilateral lower leg swelling on admission to the hospital. Diuretics have been a mainstay in the management of CHF as they have been demonstrated to be effective in decreasing 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 from 18 randomised controlled trials which involved 928 patients was conducted to evaluate the efficiency of diuretics in the treatment of CHF. It was demonstrated that the use of diuretics resulted in significantly less deaths (OR 0.25; 95% CI 0.07-0.84) compared to placebo. Subsequently, a relative risk reduction of 8% and a number needed to treat of 12.5 were also acquired from this meta-analysis. The use of diuretics also demonstrated a greater improvement in exercise performance (OR 0.37; 95% CI 0.10-0.64) compared to other drugs that are routinely used in the treatment of CHF such as ACE inhibitors and digoxin.18
A multicentre, open-label trial which involved 170 patients with NYHA class II-III CHF was conducted to evaluate the safety and efficiency of torasemide in the treatment of CHF in terms of incidence of adverse effects, improvements in NYHA class as well as symptom relief. Overall, the use of torasemide demonstrated substantial improvements in NYHA class (p < 0.001) as well as symptoms like breathlessness and paroxysmal nocturnal dyspnoea (p < 0.001). Moreover, peripheral oedema resolved in 56 of 78 patients who were oedematous at the start of the trial (p < 0.001).19
In addition, potassium supplements are often prescribed concurrently with diuretics like in this clinical case to help prevent from hypokalaemia which will predispose the patient to arrhythmias and subsequently death.9 In a recent retrospective analysis of data from the SOLVD study which was conducted by Cooper et al. to evaluate the influence of diuretics on arrhythmic death in patients with left ventricular dysfunction, the use of diuretics led to a substantial increase in the risk of arrhythmic death (p < 0.001).20
Subsequently, the patient involved in this clinical case was also prescribed with carvedilol, which is a non-selective β-blocker in addition to her treatment with valsartan and furosemide. β-blockers should be considered in patients with all NYHA classes of HF unless contraindicated by the presence of other co-morbidities such as asthma, heart block or symptomatic hypotension as they have been demonstrated to be effective in decreasing morbidity and mortality in patients with CHF when used in combination with ACE inhibitors and diuretics in numerous controlled trials.1, 2 Moreover, β-blockers should only be initiated in patients with stable CHF as they can cause worsening of CHF. Examples of β-blockers that are used in the treatment of CHF include bisoprolol, carvedilol and metoprolol.1, 8
The MERIT-HF trial is a randomised, double-blind controlled trial which was conducted to evaluate the influence of modified-released preparations of metoprolol on mortality as well as hospitalisations due to CHF in 33,391 patients with NYHA class II-IV CHF and LVEF of 40% or less. It was demonstrated that the use of modified-released preparations of metoprolol led to a relative risk reduction of 31% in mortality as well as hospitalisations due to CHF (95% CI 0.20-0.40). There were also substantially more patients who received modified-released preparations of metoprolol with improved NYHA class (p = 0.009) and quality of life (p = 0.003) compared to those who received placebo.21
A similar outcome was observed in a further randomised, double-blind controlled trial which was conducted by Packer et al. to evaluate the influence of carvedilol on morbidity and mortality in 2,289 patients with NYHA class III-IV CHF and LVEF of less than 25%. It was demonstrated that the use of carvedilol led to a relative risk reduction of 24% in mortality as well as hospitalisations due to CHF (95% CI 013-0.33; p < 0.001).22
In a recent meta-analysis of data from two large randomised clinical trial, namely CIBIS and CIBIS II which involved 3,288 patients with symptomatic CHF to evaluate the efficacy of bisoprolol in the treatment of CHF, the use of bisoprolol led to a relative risk reduction of 29% in all-cause mortality (95% CI 0.17-0.40; p < 0.001) as well as a relative risk reduction of 18% in hospitalisation due to CHF (95% CI 0.11-0.25; p < 0.001). The outcome of this trial is comparable to those observed in previous trials conducted using carvedilol and metoprolol.23
The COMET study is a further randomised, double-blind controlled trial which was conducted to compare the efficiency of carvedilol, a non-selective β-blocker and metoprolol, a selective β1-blocker in the treatment of CHF in 1,151 patients with NYHA class II-IV CHF and LVEF of less than 35%. It was demonstrated that the use of carvedilol led to a greater reduction in all-cause mortality (OR 0.83; 95% CI 0.74-0.93; p = 0.0017) compared to metoprolol. Both carvedilol and metoprolol also showed a similar reduction in all-cause hospitalisations (OR 0.97; 95% CI 0.89-1.05; p = 0.45) as well as a comparable safety profile since the number of patients who discontinued treatment with the study drug was similar for both drugs.11
The use of valsartan in this patient is appropriate since the use of ARBs as an alternative is recommended by all available guidelines in patients who are intolerant to ACE inhibitors due to its adverse effects. ARBs show similar efficacy with ACE inhibitors and they also appear to be better tolerated in numerous trials. Furthermore, the use of furosemide and carvedilol in this patient were also appropriate. Furosemide is an effective diuretic even in patients with renal impairment and is effective in relieving symptoms of CHF. It also has the advantage of being relatively inexpensive and has been in use for many years to treat CHF with minimal adverse effects. However, the patient in this clinical case requires close monitoring of her renal function and blood pressure since ARBs are known to cause renal impairment, hyperkalaemia and hypotension. She should also be counselled on the importance of compliance with her medications, fluid and sodium restriction to prevent further episodes of CHF.