Patient S.V. is a 54 years old female. She is a postmenopausal housewife and her family history is not being recorded. She is a non-smoker and does not drink alcohol at all. She has no-known drug allergic. The past medical history showed us that Madam S.V. is having, rheumatoid arthritis (RA), hypertension (HPT) for 10 years and diabetes mellitus (DM) for 7 years. She was admitted to the hospital on few weeks ago due to congestive heart failure.
Madam S.V.'s drugs history include:
IV furosemide
40mg/day
Oedema & HF
T. perindopril
4mg od
HF & HPT
T. spironolactone
25mg od
HF
T. Losec (Omeprazole)
20mg bd
Duodenal ulceration
P. Calcium lactate
1 puff od
Calcium supplement
T. Rocatriol
0.25mg bd
Vitamin D supplement
T. Metformin
500mg bd
DM
T. folate
5mg od
Folate deficiency
T. Methotrexate
20mg/week
RA
Clinical data
Patient's Full Blood Count is showed below:
RBC
5.3
1012/L
4.0-5.2
WBC
13.2
109 /L
5.2-12.4
MCH
24
pg
26-34
MCHC
29
g/L
31-37
RDW
18
%
11.5-14.5
PLT
410
109 /L
130-400
The abnormal result of FBC may due to folate deficiency that caused by side effect of methotrexate. Besides that, patient was having high neutrophil number for his differential count which is 8.7 k/µL (normal range 1.9-8.7 k/µL). This may due to the long-term use of corticorsteroid. Patient's total carbon dioxide in the blood was two times higher than normal range (23-27 Vol%). Prothrombin time and INR of the patient was low: PT =11.1 sec (normal range = 11.9-14.5 sec), INR = 0.82 (normal range 2-4). However, the reason is unknown.
Diagnosis
ECG and chest X-ray were carried out and the results showed that patient was having sinus tachycardia and cardiomegaly. Cardiovascular system of patient also had been checked. It found that the patient was having a 3rd heart sound. Hence, the patient was diagnosed with congestive heart failure (CHF).
Clinical progress
DAY 1
Patient is admitted to the hospital at 10.30am by ambulance. She is weak but conscious and alert. The patient complains that she is shortness of breath (SOB) and her sleep has been interrupted due to SOB. It can also be considered as paroxysmal nocturnal dyspnoea (PND) which is sudden, severe SOB at night that awakes a person from sleep, often coughing and wheezing.
At the same time, she also experiences from chest discomfort and swelling leg. Besides that, the patient also shows the symptoms of cushing's syndrome such as moonface and hirstuism. The blood pressure (BP) and pulse rate (PR) of Madam S.V. are found to be quite high as well, which is 118/87mm/Hg and 146b/min respectively.
Test ordered include FBC, RP, LFT, ABG, Coagulation test, U&E, CXR, ECG and random glucose test.
Nebulizer is given to patient once she is admitted. She is also on high flow mask oxygen 15L/min at the same time to ease the problem of SOB. Salfasalazine 1g bd is added to patient. The management plan is to carry out lung function test, continue to on the face mask for oxygen supply, revise all test results, restrict fluid and continue with old medications.
DAY 2
Patient still complain of minimal SOB and minimal chest pain. Another new complain, headache, has been recorded. Her BP and PR have been slowly decreased but they are still not within the normal range.
T. perindopril 4g od is added for a better control of HPT and HF. Management plan include restrict fluid < 800cc/day, strict I/O charting and off oxygen face mask.
DAY 3
Patient is no longer complaining for anything. She has no chest pain and SOB anymore. Her PR has back to normal range. However her BP is still slightly higher than normal range. Management plan is same as day 2. Sulphasalazine since the condition of RA is improved.
DAY 4
Patient is feeling well, comfortable and tolerating orally. Her BP and PR are within the normal range. The management plan is to perform a CRX report, patient can be discharged if normal result is obtained and continue old medications.
Pharmaceutical care issues
There are few things need to be taken care of in this case. Firstly, the patient is having the problem of nausea and vomiting and no action is taken to solve this problem. Antiemetic drug (H1 receptor antagonist, cyclizine; D2 receptor antagonist, halopiridol) should be given. At the same time, underlying cause of nausea and vomiting has to be identified if possible. This may caused by side effect of perindopril.
Secondly, patient is having cushing's syndrome due to long-term usage of steroids for her rheumatoid arthritis. However, there is no any record about the steroids intake for patient in clinical notes. Hence, we have to ask GP or patient to make sure that whether she has stopped taking steroids or still continue with it. According to CSM, long-term corticosteroids therapy should be withdrew gradually. Abrupt discontinuation of corticosteroids therapy may cause severe symptoms because normal production of steroids by the body has been affected. The dose may be reduced rapidly down to physiological doses (prednisolone 7.5mg daily). Then, the progress of dose reducing can be slowed down. [i] The patient is hirudism which is one of the symptoms of cushing's syndrome. This problem can be overcome by local measures such as shaving, or depilation such as using wax or cream (eg: eflornithine).4
The dose of T.folate for patient which is 5mg once daily is indicated for treatment of megaloblastic anemia. However, the FBC test result does not show any symptoms of megaloblastic anemia. The dose of T.folate should be 5mg once daily if it is indicated for folate deficiency induced by mehtotrexate. Blood film should be carried out to make sure that whether the patient is having megaloblastic anemia or not. FBC, serum folate and serum B12 are reliable indicator of folate status. Real indication of T.folate has to be clarified with doctor before dispense the drug.
Oedema problem never been improved since the day patient been admitted into the hospital. Restrict fluid intake and strict I/O charting is carried out. However, patient is not compliance to it. Some simple self-care techniques can be taught to patient to reduce the build up of fluid. Counsel the patient about the importance of following Strict I/O chart. Dose of furosemide can be increased if oedema doesn't improve.
The blood pressure of patient is still not stable yet. Patient has to be counseled to improve her diet and lifestyle. It is also necessary to monitor BP of patient regularly. Additional of β-blocker can be considered if BP is not reducing. However, due to its negative inotropic effect, β-blocker should be started in very low dose.
Lastly, upon discharge, ensure all appropriate medications are prescribed and patient is counseled appropriately. We have to tell patient that Perindopril is added in and ensure patient's compliance with medication. Patient should be told to avoid alcohol and cranberry juice and consult GP if anything goes wrong.
Disease overview
Incidence
Heart failure (HF) affects 0.3-2% of general population. In 2001, officially there are 11500 deaths are recorded in the UK due to HF. The incidence rate increase by double each decade from age 45. It affects 3-5% of those over 65 years and 8-16% of those over 75 years. The Rotterdam study shows that prevalence is higher in men compared to women. [ii] , [iii]
Pathophysiology
Heart failure can be defined as inability of the heart to supply sufficient blood flow to meet the body's needs. [iv] HF can result from any disorder that reduces ventricular filling (diastolic dysfunction) and myocardial contractility (systolic dysfunction). The leading causes of HF are coronary artery disease and HPT. As cardiac function decreases after myocardiac injury, the heart relies on few compensatory mechanisms. Although those compensatory mechanisms can initially maintain the cardiac function, they are responsible for HF symptoms and contribute to disease progression. An initiating event such as acute MI can cause the HF state becomes a systemic disease whose progression is largely mediated by neurohormones and autocrine/paracrine factors such as agiotensin II, norepinephrine, aldosterone, natriuretic peptides, and so on. Some drugs may exacerbate HF due to their inotropic, cardiotoxic and sodium-/water- retention properties. [v]
Diagnosis
A complete history, physical examination and appropriate lab testing are essential in initial evaluation of patients suspected from having HF. The signs and symptoms are the key for early detection. Breathlessness, angina, fatigue and wheeze are common signs and symptoms. Patient complains that she is having SOB and PND.
Electrocardiogram (ECG) and B-type natriuretic peptides (BNP) are essential tests for every patient with suspected HF. ECG is carried out once the patient is admitted into the hospital. Madam S.V. was detected to have sinus tachycardia by ECG which is one for the common ECG abnormalities in HF. Others common ECG abnormalities include sinus bradycardia, atrial fibrillation, ventricular arrhythmias and so on. Plasma BNP is not measured in this case.
Chest X-ray (CXR) is also an essential component of diagnostic work-out in HF. It is very useful for detection of cardiomegaly, pulmonary congestion and pleural fluid accumulation. It also demonstrates the presence of any pulmonary disease or infection that will lead to dyspnoea. Via CXR, patient is detected from having cardiomegaly which is also one of the abnormalities for HF.
Echocardiography (ECHO) should be performed shortly if one or both ECG and BNP get an abnormal result. ECHO is widely available and safe and provides essential information on aetiology of HF. However, ECHO is not carried out in this case. Some other tests such as FBC, RP, LFT, ABG, U&E and random glucose test have been carried out to exclude others possible conditions.
Pharmacology basis of drug therapy
Diuretics
The most important function of diuretic drug is to act by decreasing Na+ reabsorption. Diuretic drugs can inhibit Na+ reabsorption by actions on different transport mechanism, which are located at different sites in nephron. All diuretics are acting on the luminal surface of the nephron. They are protein bound in blood and reach the tubular fluid by secretion into proximal convoluted tubule utilizing the organic acid transport mechanism. They are mostly used to control symptoms of breathlessness and fluid retention. However, they do not alter disease progression or prolong survival. Thus they are not considered mandatory therapy for patients without fluid retention.
Loop diuretics for example furosemide is most widely used if compared to other thiazide. It produces diuresis with NaCl loss. It also has vasodilator action which is partly mediated via prostaglandin. This will increase blood flow in the medulla and hence contributes to their natriuretic effect. Unlike thiazides, loop diuretics maintain their effectiveness in the presence of impaired renal function, although higher doses may be necessary. Thizide diuretics are relatively weak diuretics and used alone infrequently in HF. However, thiazide like metolazone can be used in the combination with loop diuretic to promote effective diuresis.
Angiotensin-Converting Enzyme Inhibitors (ACEIs)
ACE is binding to the plasma membrane and can also exist as a soluble enzyme. The ACEIs act by substrate competition by binding in the Leu-His binding pocket on ACE. Thus, action of angiotensin-I is inhibited. They also decrease the concentration of angiotensin II and aldosterone and attenuating many of their deleterious effects, including reducing ventricular remodelling, myocardial fibrosis, vasoconstriction and sodium and water retention. In addition, they also very helpful in reducing blood pressure due to arterial vasodilation. However, they will inhibit the breakdown of bradykinin which contributes to strong hypotensive action and cough.
There are currently 11 ACEIs available for clinical use with similar structure and properties, including captopril, enalapril, lisinopril and others. ACEIs are indicated in all grades I to IV of heart failure which stated in NYHA. Potassium sparing diuretics should be stopped before starting ACEI. ACEIs may increase the risk of renal failure in patient with high dose diuretics, elderly, those with existing renal dysfunction and patients with grade IV HF. Hence regular renal function monitoring is required once patient has stabilized on drug.
β-blockers
β-blockers can be either selective for β1-adrenoceptor which is cardioselective such as atenolol, bisoprolol and metoprolol or non-selective which can act on both β1-and β2-adrenocepors such as propranolol and timolol. Blockade of β1-receptors will decrease rate and force of contraction of heart. Meanwhile, β2-adrnoceptor blockade inhibits adrenaline-induced vasodilatation mediated by these receptors. Via these mechanisms, heart rate and cardiac output can be reduced. Beneficial effects of β-blockers may result from antiarrhythmic effects, slowing ventricular remodelling, decrease myocyte death, improving LV systolic function, decreasing heart rate, and ventricular wall stress.
The use of β-blockers is not suitable for patients who have unstable HF. Patients should receive a β-blocker even if symptoms are mild or well controlled with ACEI and diuretic therapy. Because of negative inotropic effects of β-blockers, they should be started in very low doses with slow upward dose titration to avoid any symptomatic worsening. β-blockers may worsen HF in the short term, but if use with caution they may be very useful in preventing long-term deterioration.
Angiotensin receptor blockers (ARBs)
ARBs compete with angiotensin-II and block angiotensin-II receptor (AT1). Hence, deleterious effect of angiotensin-II is prevented. ARBs may be used as an alternative to ACEIs (eg: losartan) when patient is intolerant to ACEIs or may be used as adjunct therapy (eg: valsartan and cadesartan) in patient who remains symptomatic despite the dose of ACE and β-blockers have been optimised. However, combination of ACEIs and ABRs increase the risk of renal dysfunction and hyperkalaemia.
Aldosterone antagonists
Aldosterone antagonists such as spironolactone and eplerenone block the mineralcorticoid receptor, which is the target site of aldosterone in kidney, aldosterone antagonists inhibit Na+ reabsoption and K+ excretion. However, the diuretic effects are minimal. Spironolactone can be added to ACEI, diuretic and digoxin to improve morbidity and mortality in patient with sever HF. Eplerenone has been shown to reduce morbidity and mortality in patient with left ventricular dysfunction post-MI.
Digoxin
Digoxin is the glycoside in widest clinical use. It has narrow therapeutic index. Digoxin attenuates the excessive sympathetic nervous system activation in HF patient by reducing central sympathetic out flow and improving impaired baroreceptor function. It also increases parasympathetic activity in HF patients and decreases heart rate. Thus diastolic filling enhanced. Digoxin does not improve survival rate but it does provide symptomatic benefits. It is primarily used to treat atrial fibrillation but it has been shown to improve symptoms in patients in sinus rhythm with HF.
Vasodilators (hydralazine/isosorbide dinitrate)
This combination only used if all other treatment options above have been excluded. Nitrates are venodilators which producing reductions in preload. Hydralazine is direct vasodilator that acts predominantly on arterial smooth muscle to reduce systemic vascular resistance and increase stroke volume and cardiac output. The problems faced by this combination include frequent dosing, high frequency of adverse effects and increased cost.
Evidence for treatment of the conditions
Diuretics
Diuretic is a very important drug for heart failure treatment especially for symptoms of fluid retention. A meta-analysis of randomised controlled trials of diuretic therapy has shown that diuretics not only improve the symptoms and exercise capacity of patient with congestive heart failure (CHF), it also reduces the risk of deterioration of disease. [vi] Cochrane database indicated that diuretics also reduce the mortality rate compared to placebo. [vii]
Another study about the withdrawal of furosemide had proven that signs and symptoms of heart failure had exacerbated (impaired quality of life, weight gain and walking distance reduced) after diuretic therapy was stopped. [viii] Higher dose of furosemide will have more desirable effects such as increasing general well-being and reducing symptoms of disease. [ix] However, the inappropriate high dose of furosemide will lead to hypotension. The risk of hypotension will be increased if patient on ACEIs or vasodilators at the same time with diuretics. According to NICE guidelines, low dose should be prescribed for the initiation of therapy and titrated up according to patient's condition.
Furosemide is the most commonly used loop diuretic. However, some patients are more responsive to other loop diuretic such as torasemide. This may due to its longer duration of action and high absorption. [x] Some pharmacoeconomic analyses also proved that torsemide reduces hospitalisation for patient with CHF. Hence, overall treatment costs are reduced although torasemide is more expensive than furosemide. Patients that treated with torasemide have improved their quality of life. The data also suggest torasemide to be used as first-line treatment for patients with CHF and for those who are not response to furosemide. [xi]
Angiotensin-Converting Enzyme Inhibitors (ACEIs)
There are five long-term randomised trials showed that mortality rate has been reduced by 23% (odds ratio 0.74 [95% CI 0.66-0-83]), rate of readmission of heart failure reduced by 35% (0.73 [0.63-0.85]) and rate of re-infarction had been reduced by 26% (0.79 [0.70-0.89]) as well in patients with heart failure or left-ventricular systolic dysfunction who assessed ACEIs compared to placebo group. The benefits of ACEIs were observed at the beginning of therapy and persisted long term. [xii] , [xiii]
In SOLVD investigation, ACEIs (enalapril) reduced the rate of hospitalisations and also incidence of heart failure in patients with reduced left ventricular ejection fractions compared to placebo group. [xiv] Some randomised controlled trials proved that ACEIs also improve the exercise capacity and quality of life in majority of the patients. Not all the patients with heart failure due to left-ventricular systolic dysfunction experienced the improvement of exercise capacity. [xv] , [xvi] However, ACEIs alone is not enough for the treatment of heart failure with pulmonary oedema. Diuretic is needed to maintain sodium balance and prevent any fluid retention. [xvii] ACEIs are more often to be prescribed compared to vasodilators and angiotensin receptor blockers due to more evidence supports. [xviii] , [xix]
ACEIs will cause hyperkalaemia, cough and deterioration of renal function. Hence, renal function and serum potassium level need to be checked before the treatment is initiated. The SOLVD data, a randomised, double-blind and placebo controlled trial with 3379 patients, proved that enalapril caused 33% increased in deterioration of renal function compared to control group (P = 0.03). [xx] There is another study (n=191) showed that 44% of patients taking ACEIs suffered from persistent cough compared to controls which is only 11.1% (P<0.001). NICE guideline indicates that ACEIs is cost effective. This may due to low rate of hospitalisation.
β-blockers
The European Journal of Heart Failure suggested that β-blockers should be prescribed to all patients with symptomatic HF and when left-ventricular ejection fraction ≤ 40%. There are few meta-analyses have been carried out which included large amount of clinical trials. β-blockers showed significantly reduction of overall mortality by 22% (95% CI=16%-28%) that caused by sudden death and left ventricular function. [xxi] The hospitalisation rate also has been reduced by 24% (95% CI=19%-29%). [xxii]
Most of the survival benefits for patient with NYHA class II and III are well documented. There is a meta-analysis had proven that β-blockers are having the same improvement of survival rate among the patients with severe HF compared to patients with NYHA class II and III. Further studies need to be carried out to evaluate overall benefits versus risks of treatment in NYHA class IV. [xxiii] There are three main studies, n≈9000, had been carried out to compare the efficacy between β-blockers (bisoprolol, metoprolol succinate CR, carvedilol) and placebo. Almost 90% of patients involve in there three randomised trials were on ACEIs or ARB. Most of them also took diuretics and digoxin. All trials showed the improvement of mortality rate (RRR= 34%), risk of hospitalisation (RRR= 28-36%) and self-reported well being. [xxiv] , [xxv] So far, there are no significant differences between selective and non-selective β-blockersxxi, [xxvi] and those with or without vasodilating properties.xx
In one randomised controlled trial (COMET), n=3029, carvedilol was used to compared with the efficacy and clinical outcome of metoprolol tartate. The result has shown that carvedilol reduced the mortality rate significantly among the patients compared to short-acting metoprolol tartate (P=0.0017). [xxvii] However, there is no any clinical trial about comparison between carvedilol and long-acting metoprolol succinate. There is little economic evidence can be found for β-blockers. NICE guidelines suggested that β-blockers are cost effective due to reduction of hospitalisation rate.
Angiotensin receptor blockers (ARBs)
ARB is a good alternative for those who cannot tolerate ACEIs due to side effects. However, there is no significant improvement in mortality rate if compared to ACEIs therapy for patients with HF due to LVSD. [xxviii] , [xxix] A meta-analysis with 17 trials, n=12469, showed that combination of ARBs and ACEIs has a superior effect in reducing the rate of hospitalisation (odds ratio: 0.74, 95% CI: 0.64-0.86) but not in life expectancy.xxvii
2548 patients with CHF (NYHA class II-IV) and left-ventricular ejection fraction ≤ 40% were included in the CHARM-Added trial to test the clinical outcomes of candesartan. The result showed that the addition of candersatan reduced risk of mortality and hospitalisation by 15% compared to placebo. Another similar randomised trial, Val-HeFT (n=5010), also proved that addition of valsartan to previously prescribed therapy (ACEIs and β-blockers) significantly improve clinical signs and symptoms, ejection fraction and patient's quality of life. It also reduced rate of hospitalisation but not mortality rate. Through this trial, post hoc analysis suggested that the combination therapy among ACEIs, ARBs and β-blockers will cause significant adverse effect on mortality and morbidity. This triple combination should be avoided until the further studies are carried out. [xxx]
Another result from VALIANT, n=14703, showed that valsartan has the same effect as ACEIs for patients with HF, LVSD, or both in myocardial infarction. [xxxi] However, in another trial which is similar to VALIANT (OPTIMMAL), losartan was showed not as effective as ACEIs. [xxxii] There is no economic evidence for usage of ARBs as HF treatment in UK.
Aldosterone antagonists
Spironolactone is the most common aldosterone antagonist used in treatment of HF. In a double-blind study (RALES), 1663 patients with severe HF (NYHA class III and IV), left ventricular ejection fraction ≤ 35% and being treated with diuretics, ACEIs or digoxin were recruited to test the effectiveness of spironolactone on their morbidity and mortality. The result showed 30% reduction in mortality rate (RRR=0.70; 95% CI= 0.60-0.82; P<0.001) and 35% reduction of frequency of hospitalisation (RRR=0.65; 95% CI=0.54-0.77; P<0.001) compared to placebo group. There was no hyperkalaemia problem occurred in this trial. [xxxiii]
A selective aldosterone antagonist, eplerenone, has fewer side effects compared to spironolactone. A randomised controlled trial (EPHESUS), n=6633, proved that morbidity and mortality rate among patients with left ventricular dysfunction after acute myocardial infarction had been reduced with the addition of eplerenone compared to placebo group. [xxxiv] There is no relevant economic evidence of aldosterone antagonist.
Digoxin
A Cochrane review, n=7896, proved that digoxin reduced 23% of hospitalisation rate and 64% improvement of the symptoms compared to placebo. However, digoxin did not influence the mortality rate. [xxxv] Another randomised control trial (DIG study) also supported that digoxin reduced hospitalisation rate (RR=0.88; 95% CI 0.77-1.01; P=0.06) but not overall mortality. In DIG study, β-blockers and spironolactone were not introduced to patients for the treatment of HF. Thus, a more concrete result can be obtained. [xxxvi]
There are some other placebo-controlled trials had shown that digoxin improved quality of life and exercise tolerance of patients with mild to moderate HF. Patients discontinued the digoxin treatment showed deterioration in maximal exercise capacity compared to patients who still under digoxin treatment. The result of PROVED trial showed withdrawal of digoxin also increased rate of hospitalisation and worsen the left ventricular systolic function. [xxxvii] The withdrawal of digoxin will cause more significant effect in patients with severe HF (NYHA class IV) and low left ventricular ejection function. [xxxviii]
Although digoxin has narrow therapeutic index, digoxin toxicity is rarely occurs in clinical trials. The most common side effects that experienced by patients during clinical trials were GI disturbance and arrhythmias.xxxvi There is no evidence for the relationship between dosage of digoxin and therapeutic effects. In addition, higher dosage may produce more side effects. A study from US suggested that digoxin may be cost effective to be used as treatment of HF. [xxxix]
Vasodilators (hydralazine/isosorbide dinitrate)
A randomised, double-blind clinical trial had been carried out to study the effect of high dose of transdermal nitroglycerin (GTN) for patients with HF and treated with ACEIs. Result showed that GTN improved exercise capacity and left ventricular systolic function in patients. However, this study is not valid due to small sample size, n=29.
There are more clinical trials have been carried out to study the therapeutic effect of combination between hydralazine and isosorbide dinitrate (H-ISDN). One of the studies, n=642 men, proved that addition of H-ISDN had reduced mortality rate by 36% for patients with chronic CHF within 3 years. Left ventricular function also significantly improved in H-ISDN group compared to placebo. [xl] Comparison between H-ISDN and ACEIs (enalapril) among patients with chronic CHF showed that H-ISDN is not as effective as ACEIs since enalapril reduced mortality by 28% (p=0.016). [xli]
In A-HeFT, 1050 black patients with NYHA class III or IV accompanied by dilated ventricles had been recruited to study whether H-ISDN provides additional benefit to blacks. H-ISDN showed 43% reduction in mortality (ARR=4%; NNT=25; P=0.01) and 33% reduction in hospitalisation rate (P=0.01). [xlii] However, the compliance of patients with H-ISDN is generally poor. This is due to high incidence of adverse effects which includes headache and GI disturbance. H-ISDN also will cause lupus-like syndrome but it is rarely occur. [xliii]
Conclusion
In this case, the treatment of HF include
