Combination Therapy for Heart Failure - Essay Example

A critical review on combination therapies: Beta-blockers +ace inhibitors and endothelin receptor antagonist + ace inhibitors as combination therapies for heart failure Course: Lecturer: Date Table of Content ABSTRACT 2 INTRODUCTION 3 Background to the Study 3 Purpose of the Study 4 Research Questions 4 Significance of the Study 4 LITERATURE REVIEW 5 Literature Search Approach 5 Current trend in cases of heart failure 6 Systolic Dysfunction in Heart Failure: Neurohormonal Theory 7 Beta blocks and their functions 8 ACE inhibitors and their functions 9 Endothelin receptor antagonists and their functions 10 RESULTS 11 Selection of Patients for Beta-Blockers and ACE Inhibitor combination 12 Selection of Patients for ACE inhibitors and endothelin Receptor Combination 13 Patient Factors to consider when choosing a combined therapy 15 Preference for beta blocker and ACE inhibitor combination therapy over ACE inhibitors and endothelin receptor antagonists combination 16 DISCUSSION 19 The need for a combination therapy 19 Reason for using ACE inhibitors as a constant in both therapies 19 Selection of ACE inhibitors and beta-blocker over ACE inhibitors and Endothelin Receptor antagonists 20 Management of side effects and concomitant therapy 21 CONCLUSIONS 22 Summary 22 Conclusion and Suggestion for future work 23 EXPERIMENTAL 24 References 25 Appendix 27 List of Tables Patient Selection for Beta Blocks 13 Overview of Patient Response to ACE Inhibitors and endothelin receptor combination 14 Patient Factors for combined therapy 15 Beta-blockers and ace inhibitors as combination therapy for heart failure or endothelin receptor antagonist and ace inhibitors as combination therapy for heart failure ABSTRACT Heart failure is one of the most deadly diseases known to man It is also preventable and treatable where appropriate therapies are applied. The study was conducted with an understanding of the efficacy of three major interventional drugs namely ACE inhibitors, beta blockers, and endothelin receptor antagonists. Through practical clinical experiments, each of these interventions has been found to possess considerable levels of efficacy with the treatment of heart failure. The rates of success with singular usage of these therapies have been lamented as being highly inadequate. A new paradigm was therefore taken to combining the three independent interventions in a manner that mad the presence of ACE inhibitors constant. The resulting combined therapies that were produced were ACE inhibitors and beta blockers, ACE inhibitors and endothelin receptor antagonists. Different tests were conducted on patients with heart failure to find out the most preferred inclusion and exclusion criteria that work for different patients when attempting to use any of the combined therapies. This critical review showed that when used independently, the three therapies produced less effective results as compared to combined therapies, with the combination therapy applying ACE inhibitors and beta blockers being the more effective combination therapy than ACE inhibitors and endothelin receptor antagonists. INTRODUCTION Background of the Study Cardiovascular diseases are considered one of the major health issues afflicting a significant degree of the human population. This disease has high mortality rates and has been known to lead to various health complications. However, for the most part, this disease is also very much preventable and manageable. In the current setting where different major health advancements have been made and evidence-based practice highlights the importance of preventative medical care, the management of this disease has significantly improved. The primary prevention for cardiovascular diseases has been prioritized by the World Health Organization. Primary prevention includes the adoption of a healthy diet and the participation in physical activities. Pharmacological management, mostly through beta blockers and ace inhibitors have been recommended for heart failure. Heart failure, otherwise known as congestive heart failure is one of the possible outcomes of cardiovascular diseases. In instances when it is not immediately managed and resolved, it can be potentially fatal. Due to the fatal nature of the disease, health authorities have expanded the research and development for CVDs and CHF, especially in terms of effective treatment and interventions for the disease. Some of these developments include combination therapies which ultimately seek to manage the symptoms of the disease as well as to prevent fatal outcomes of CHF. In a recent study by Raya, Gay, Aguirre and Goldman (2009), it was pointed out that single interventions to heart failures have only been effective in controlling the signs and of the disease, but these interventions are not effective in improving CHF outcomes. As such, combined therapies have been suggested as better options for patients. In these therapies, two independent management solutions are combined as a single effective treatment for heart failure. In the current study, two of the most commonly used combined interventions will be discussed and evaluated. These two combined interventions are: (1) beta blockers and ace inhibitors, and (2) endothelin receptor antagonist and ace inhibitors. These therapies shall be tested against each other in order to establish which combination therapy is more effective in managing CHF. Purpose of the Study The purpose of this study is to compare two combination therapies for CHF, specifically (1) beta blockers and ace inhibitors, and (2) endothelin receptor antagonist and ace inhibitors. The study will examine the effectiveness and weaknesses associated with each of the two combined interventions. Various clinical experiments and research evaluating these two forms of interventions shall be critically examined. At the end of the study, it is expected that important findings will be made on which of the two interventions is most effective in managing and improving outcomes for CHF. Research Question: Between the use of combination therapies: (1) beta blockers and ace inhibitors, and (2) endothelin receptor antagonist and ace inhibitors, which form of therapy is more effective in managing CHF and improving its disease outcomes? Specifically, it shall answer the following subquestions: 1. 2. What are the independent functions of ACE inhibitors, beta blockers and endothelin receptor antagonist? 3. How do the combination therapies: (1) beta blockers and ace inhibitors, and (2) endothelin receptor antagonist and ace inhibitors work in relation to CHF? 4. What unique advantages exist for the use of any of ACE inhibitors and beta blockers, and ACE inhibitors and endothelin receptor antagonist as therapies over the other? 5. What are the disadvantages of using either form of therapy in managing CHF? Significance of the Study The current study is being conducted in order to support evidence-based practice, specifically evidence-based practice in the management of CHF. Evidence critically evaluated for this study shall help practitioners prepare specific and effective interventions for patients with CHF or those at risk for CHF. This study shall help shed light on the most effective combined therapy for heart failure (Capasso and Anversa, 2002). While there are some existing studies on heart failure, major gaps in research and literature will likely be seen, and this study shall seek to fill in such gaps in order to establish the best evidence in ensuring CHF treatment. This study shall also establish major advantages and best practices associated with the use of ACE inhibitors and beta blockers, and ACE inhibitors and endothelin receptor antagonist as therapies. LITERATURE REVIEW Literature Search Approach The research was conducted following the secondary data collection approach. Under such approach, a literature search was conducted applying systematic methods using an inclusion and exclusion criteria. As part of the literature search, the researcher identified five (5) major criteria in determining studies to be included in the literature review for the study. The five major criteria included: (1) studies on combined therapies, specifically on ACE inhibitors and beta blockers, or ACE inhibitors and endothelin receptor antagonist (2) studies less than 10 years old (3) sourcesin the English or European setting (4) sources published in English and (5) sources recommended for use by one or more universities. Having outlined the inclusion criteria for the work, the researcher then went on to gather data from books, articles, news sources, and online sources using the inclusion criteria. The initial search involved a quick skimming process through the titles and table of contents of the sources to ensure that they satisfied the inclusion criteria. Studies which were not accessible and which only presented abstracts were not included in the literature search. As a result, the studies were further narrowed down to the best 20 sources. These sources were fully available and fulfilled the inclusion requirements These sources were subsequently reviewed for secondary data collection, the outcome of which has been presented below. After the studies were narrowed down to 20, themes were extracted from these studies. Some of these themes include the trends in heart failure, systolic dysfunction in heart failure, beta blocks and their functions, ACE inhibitors and their functions, and endothelin functions. Current trends in cases of heart failure There are different statistics, trends, and developments in CHF. In the study by , Pfeffer, Pfeffer, Steinberg and Finn (2005), they note that heart failure remains the only cardiovascular disease that continues to record increasing incidence in risk factored people all across the globe. Similarly, Sweet, Ludden, Stabilito , Emmert and Heyse (2008) observed that CHF has a significant mortality rate and comes with several economic burden due to the demands of its treatment and management. Generally, a person is said to be suffering from heart failure when there is a deficient action of the heart in terms of providing sufficient pump action, essential for blood flow to the different parts of the body (Schoemaker, Debets, Struyker-Boudier and Smits, 2001). The heart is constantly expected to go through several pump actions in order to send oxygenated blood to all parts of the body. Due to various factors and causes, such functional role can become impaired, likely leading to congestive heart failure or congestive cardiac failure. Some of the most common causes of heart failure include ischaemic heart disease, hypertension, cigarette smoking, valvular heart disease, obesity, dilated cardiomyopathy, and diabetes (Alam, Rezkalla, Farkas and Turi, 2002). Van, De Graeff, Wesseling, and Langen (2006) however argue that people of different geo-cultural backgrounds are likely to have different risk factors relating to health disease. More often than not, physical examinations and assessments may help detect the presence of heart disease. However, a confirmatory test, namely, echocardiography is recommended for a more accurate diagnosis of CHF. Among individuals diagnosed with this disease, common signs and symptoms include, shortness of breath, exercise intolerance, leg swelling, and cardiac asthma (Liang et al, 2002). Systolic Dysfunction in Heart Failure: Neurohormonal Theory There are three major types of heart failure, namely left-sided failure, right-sided failure and biventricular failure (Ertl, Kloner, Alexander and Braunwald, 2012). In left-sided failure, the patients are known to have left ventricular systolic dysfunction. The emphasis of this study is on left ventricular systolic dysfunction as it is the commonly reported case of heart failure (The CONSENSUS Trial Group, 2007). The treatment of the dysfunction will also be approached from two perspectives, first, is the combination of ace inhibitors and beta blockers and second is the use of ace inhibitors and endothelin receptor antagonist. Generally, systolic dysfunction has been identified as a mechanical defect, where there is a decreased mechanical functional cardiac activity, mostly a a decreased ejection fraction. Cohn et al (1991) warned that once the decreased ejection fraction sets in, the heart cannot anymore pump oxygenated blood to various peripheral tissues. Systolic dysfunction manifests easily in heart failure due to the fact that this dysfunction leads to hemodynamic and physiologic abnormalities which directly impact on cardiac activity, including “decreased cardiac output, elevated pulmonary capillary wedge pressure and decreased exercise tolerance” (Chavey, 2010). Haven identified necrosis, fibrosis and apoptosis as important functional components of the heart; the neurohormones hypothesis have been considered crucial in the progression of heart failure with neurohormones stimulating necrosis, fibrosis and apoptosis in the heart (Chavey, 2010). By neurohormonal theory, the need to use various forms of inhibitors to block various neurohormonal processes is advocated especially as there evidence of a positive clinical impact for patients diagnosed with heart failure disease (The SOLVD Investigators, 1991). Beta blockers and their functions As a class of drugs, beta blockers generally function by targeting the beta receptors, found on various cells of the cardiovascular and nervous systems (The SOLVD Investigators, 1992). Some of these cells are found on the kidneys, arteries, heart muscles, sympathetic nervous system, smooth muscles, and the airways. Beta blockers have for long been associated with heart failure because of the fact that the beta receptors, which are targeted by these drugs directly act on the heart. Pfeffer et al (2012) argued further that the functioning of the beta receptors are directly linked to some functional deficiencies in patients with heart failure. As part of their functions, beta blockers would generally block norepinephrine and epinephrine (adrenaline) from attaching to the beta receptors found on the cardiovascular and nervous systems (AIRE et al, 2013). Explaining why beta blocks would attempt to break the bonding between norepinephrine and beta receptors, The TRACE Study Group (2004) stated that norepinephrine and epinephrine serve as neurotransmitters which help nerves communicate with each other. By limiting their activity with the beta receptors, they can reduce heart rate, decrease blood pressure, and constrict air passages. A number of beta blockers are used in medical practice, including acebutolol, atenolol, betaxolol, bisoprolol fumarate, carteolol, carvedilol, nadolol, and metaprolol (Ogbru, 2013). Beta blockers have been found as highly effective in some diseases and health situations including, but not limited to the management of, abnormal heart rhythm, high blood pressure, heart failure, tremor, migraines, and pheochromocytoma (Ogbru, 2013). ACE inhibitors and their functions Angiotensin-converting-enzyme inhibitors (ACE inhibitors) ate drugs that help inhibit the activity of the enzyme ACE (Swedberg et al, 2012). The primary target of ACE inhibitors is the enzyme ACE Gruppo Italiano (1994) found that ACE inhibitors target the suppression of angiotensin I in the blood. Further, it has been explained that angiotensin is responsible for the formation of angiotensin II, which acts as a potent chemical produced by the human body and causing the muscles surrounding the blood vessels to contract, thereby narrowing the vessels (Ogbru, 2013b). As blood vessels are narrowed, pressure on the blood vessels is also increased, creating room for conditions of high blood pressure or hypertension to develop. Once ACE inhibitors target angiotensin I, angiotensin II would not be released and blood pressure does not increase. ACE inhibitors have therefore been common as a pharmaceutical drug for the management of hypertension and congestive heart failure. Both hypertension and CHFhave been directly associated with compromised heart functions (ISIS-4 Collaborative Group, 2005). As soon as ACE inhibitors are introduced into the body, ACE inhibitors functions by causing the dilation of blood vessels and helping reduce blood pressure. Most pharmacists would however not prescribe ACE inhibitors as a lone drug, mostly it is indicated in combination with other medications including beta blockers and calcium channel blockers (Chinese Cardiac Study Collaborative Group, 2005). Benazepril, captopril, enalapril, fosinopril, lisinopril, trandolapril, ramipril, and quinapril are all examples of commonly prescribed ACE inhibitors (Ogbru, 2013 b). Endothelin receptor antagonists and their functions The blood stream and other key organs including the kidney have been found to exhibit G protein-coupled receptors, known as endothelin receptors (Capasso and Anversa, 2002). These endothelin receptors come in four major forms, and they all play independent and complementary roles in the functioning of key systems, particularly the cardiovascular and renal systems. The four endothelin receptors include ETA, ETB1, ETB2 and ETC (Raya, Gay, Aguirre and Goldman, 2009). Swedberg et al (2012) found that when endothelin receptors are activated, they increaseintracellular-free calcium. Meanwhile, such activities, particularly in the ETA lead to contraction of the blood vessel walls, resulting to increased vasoconstriction. Such contractions and the subsequent retention of sodium leading to an andincrease of blood pressure as normal functioning of heart’s pumping action is inhibited (Ertl et a, 2012). Due to this effect of endothelin receptors on the cardiovascular system, it is always important to establish means by which their functions can be suppressed. Endothelin receptor antagonists seem to provide such suppressant functions, mostly in blocking endothelin receptors (Chinese Cardiac Study Collaborative Group, 2005). By implication, endothelin receptor antagonists function mainly by ensuring that the activation of G protein-coupled receptors in patients are either blocked or suppressed. Patients with heart failure would be identified as people having heart functional problems, where their heart cannot effectively pump blood to other parts of the body. Due to this deficiency, intracellular calcium levels increase, leading to vasoconstrictions which can lead to fatal heart failure. Very often, the active participation of endothelin receptors in the body will retain sodium, starting off the first process of increased blood pressure. Endothelin receptors have therefore been found to possess the functions of reducing the concentration of retained sodium so as to ensure that a preventive approach to blood pressure is gained. RESULTS This section seeks to interpret some of the findings relating to the application of ACE inhibitors and endothelin receptor combination therapy, and beta blockers and ACE inhibitor combination therapy for CHF. The results here shall be presented as themes based on common results and ideas presented in the studies included in this review. Application of Beta-Blockers and ACE Inhibitor combination Studies conducted by Chavey (2010) tested the use of beta-blockers and ace inhibitor combination on a number of patients. In their study, there were three major categories of respondents which applied the New York Heart Association (NYHA) Functional Classification. The first group included those who responded positively to beta blockers and ACE inhibitor combination, the second group included those who responded asymptomatically to beta blockers and ace inhibitor combination, and the last group included those who could not tolerate beta blockers and ACE inhibitor combination. Further clinical investigations showed that patients with various forms of NYHA class II or class III symptoms of heart failure caused by left ventricular systolic dysfunction found beta blocker therapy to be highly appropriate (Chavey, 2010). For these patients, their tolerance and positive reactive levels is an indication of the fact that they could be on beta blockers and ACE inhibitor combination in order to establish better outcomes and decreased cases of hospitalisations (Raya, Gay, Aguirre and Goldman, 2009). On the part of patients under NYHA class I, the use of beta blockers was found to be inconclusive. This is because some of the patients showed tolerable levels of improvement in symptoms, while others did not experience any improvement in symptoms. For those which showed no improvements at all, no adverse effects were recorded. Further clinical investigations on this group found that “asymptomatic patients with left ventricular dysfunction have had a myocardial infarction sometime in the past” (Chavey, 2010). They also had conditions such as hypertension, which the beta blockers and ace inhibitor combination attempted to treat. As with patients with NYHA class IV symptoms, the beta blockers and ace inhibitor combination was found to be highly intolerable. They were then stopped during the initiate hours of introduction. Table 1 summarises these findings. Table 1: Patient Selection for Beta Blocks Type of Patient Tolerance and Efficacy Level NYHA class I symptoms Tolerable but may not be highly effective in treating symptoms NYHA class II symptoms Tolerable and improves symptoms of heart failure NYHA class III symptoms Tolerable and improves symptoms of heart failure NYHA class IV symptoms Not tolerable and must be discontinued early Application of ACE inhibitors and endothelin Receptor Combination Latini et al (2005) used ACE Inhibitor and endothelin receptor combination on 6090 patients with myocardial infarction, randomly selected. These patients were categorised into patients with advanced CHF, patients with less severe heart failure, and those with asymptomatic LV dysfunction of any origin. For the sake of clinical trial classifications, Myocardial Infarction groupings were used. These included small trials, namely CONCENSUS-II, GISSI-3, ISIS-4, and CCS-1. The detailed meanings of these categories have been provided at the appendix. In table 2, the effect of ACE inhibitors and endothelin receptor combination in the various categories of patients have been presented. Table 2: Overview of Patient Response to ACE Inhibitors and endothelin receptor combination Source: Latini et al (2005) From table 2, it would be noted that there was an average of 4.6 lives saved per 1000 patients treated. In all trials, mortality rates were significantly reduced except in the case of CONCENSUS II, where no significant 1-month mortality rates were recorded in enalapril-allocated patients. It would be noted however that in each of the trials, the researchers introduced the ACE inhibitors to patients in the first 24 hours after AMI by intravenous (IV) infusion (Latini et al, 2005). After this, oral administration of the drugs was carried out for a period of 6 months. These findings thus point out that ACE inhibitors and endothelin receptor combination is highly tolerable in larger groups of patients as they are able to produce highly favourable effects on a multi-variable scope of clinical indicators including mortality and LV function. These records remained the same even in patients who had been identified as at risk for post-AMI. Patient factors in relation to combined therapy Even though the use of combined therapy may promise more useful results than single therapies, studies by Chinese Cardiac Study Collaborative Group (2005) showed that there are some key factors that ought to be considered when selecting patients for combined therapy. Ramahi (2010) details some of these key factors as presented in the table below. Table 3: Patient Factors for combined therapy Appropriate Patients for combined therapy Inappropriate patients for combined therapy 1. Patients with symptoms of systolic left ventricular dysfunction that is recorded in fraction of 40 percent or less. 2. Patients who are experiencing stable circulation that is free from progressive fluid accumulation and worsening cardiac output. 3. Regardless of degree of ventricular dysfunction, only patients with NYHA functional class II and III are considered appropriate as these patients have mild to moderate impairment. 4. Patients who record systolic blood pressure greater than 90 mm Hg. 5. Patients with heart rates greater than 60 beats per minute. 6. Patients who exhibit second- or third-degree heart block. 7. Patients who have not had any contraindications to any of beta blockers, ACE inhibitors or endothelin receptor antagonists 1. Patients with severe heart failure who have been found intolerant to combined therapy for treatment. 2. Patients who are Inotrope-dependent exhibiting circulation that requires intravenous inotropic support, such as dobutamine [Dobutrex]. 3. Combined therapy has been considered effective for patients with stable “compensated” circulation. To this end, patients who have been hospitalised or have immediately resumed hospitalisation are considered inappropriate for combined therapy. 4. Once patients have chronic heart failure, combined therapy becomes inappropriate. This means that patients without systolic dysfunction must not be treated with combined therapy. Preference for beta blocker and ACE inhibitor combination therapy over ACE inhibitors and endothelin receptor antagonists combination The results indicated that most experimenters and medical practitioners preferred the combined use of ACE inhibitors and beta blockers over the combined use of ACE inhibitors and endothelin receptors. The table below simplifies results outlining the merits of using the combined therapy of beta blocker and ACE inhibitors against the demerits of using the combined therapy of ACE inhibitors and endothelin receptors antagonists. Merits of ACE inhibitors and beta blocker combined therapy Demerits of ACE inhibitors and endothelin receptor antagonists 1. The ACE inhibitors and beta blocker combination has been found to be effective in the treatment of other symptomatic effects of heart failure including renal progression and respiratory dysfunction (Capasso and Anversa, 2002). 2. Beta blockers have been found to be more effective blockers when compared to endothelin receptor antagonists, in terms of decreasing the heart’s demand for oxygen. To this end, this combined therapy acts more independently even when not supported with other interventions (Chinese Cardiac Study Collaborative Group, 2005). 3. This combined therapy has been recommended and praised for its preventive and curative potency, meaning that it can be used as both a long term intervention for prevention and a short term intervention for the treatment of heart failure. 4. Beta blockers have been particularly admired for its inclusiveness when tackling mainstay treatment of congestive heart failure, which means that when combined with ACE inhibitors, their effect on variables causes of heart failure proved more effective (Pfeffer et al, 2012). 5. Once combined, this combined therapy has been said to act as an all-around cardiovascular protector, treating cases of heart failure, high blood pressure, angina, abnormal heart rhythms, and heart attack, instead of being selective with treatment (Ertl et a, 2012). 1. The combined therapy is not effective for other symptomatic effects of heart failure, such as proteinuria in renal progression (Raya, Gay, Aguirre and Goldman, 2009). 2. This combined therapy has not been independently effective in managing most forms of heart failure unless combined with novel interventions such as RAS blockade, mineralocorticoid receptor blockade and renin inhibitors. 3. Because of the presence and effect of endothelin receptor antagonists on the retention of sodium, which is rather a preliminary situation in blood pressure, this combined therapy has been found to be more effective for preventive cases of heart failure rather than the management and treatment of heart failure. 4. Endothelin receptor antagonists, which have become highly dominant in this combined therapy has been criticised as being highly selective with the various types of endothelin receptors namely ETA, ETB1, ETB2 and ETC. 5. This combined therapy has been said to be abysmal in the treatment of some forms of heart failure, particularly congestive heart failure, even though it may be effective with pulmonary arterial hypertension. DISCUSSION The need for a combination therapy The researcher has presented evidence on the preferred use of combined therapy instead of single therapy in the treatment of heart failure, especially in cases of depressed left ventricular systolic function. As noted by Pfeffer and Braunwald (2000), each of the three therapies that were presented by the researcher addressed selective symptoms of heart failure. There are also several limitations in the the selection of patients in each of the therapies presented. In response to these two weaknesses, the combined therapy has been justified as a very useful means of addressing the situation. In the first place, a combined therapy ensures that there are several symptomatic effects of heart failure that are effectively treated with the use of combined therapy (Pfeffer et al, 2012). Secondly, using combined therapy ensures that a larger patient scope can be included for treatment in every single therapeutic attempt to treat patients with heart failure. This will be far better than cases in which only limited numbers of patients can benefit from a particular therapy because the exclusion criteria on that therapy may be unfavourable to a larger population. Reason for using ACE inhibitors as a constant in both therapies Throughout this research, angiotensin converting enzyme (ACE) has been maintained as a therapy to be paired with other forms of therapies. Secondary research conducted by (Swedberg et al, 2012) showed that ACE inhibitors therapy presented the highest potential in comparative therapies, and in ensuring symptomatic improvements in patients suffering from heart failure. This was also seconded by Capasso and Anversa (2002) who argued that in comparison with other therapies, ACE inhibitors have been able to actually guarantee reduced hospitalisation and a higher assurance of survival for patients with heart failure. It is based on these factors, that ACE inhibitors were used as a constant therapy in combination with either beta-blocker or endothelin receptor antagonists. Increasing efficiency is one of the ways of ensuring that patients who depend on combined therapies would have a better chance at recovery, especially for those with depressed left ventricular systolic function. Selection of ACE inhibitors and beta-blocker over ACE inhibitors and endothelin eceptor antagonists In the study by Pfeffer and Braunwald (2000), the authors noted that both ACE inhibitors and endothelin receptor antagonists seem to focus on the same symptomatic variables among patients with heart disease. What this means is that using a list of symptomatic dysfunctions in patients as basis, the combination of ACE inhibitors and endothelin receptor antagonists will result in lesser symptomatic dysfunctions. Meanwhile, the functioning of beta-blockers and ACE inhibitors are totally independent of each other (Swedberg et al, 2012). By implication, this combined therapy will ensure and guarantee that several symptomatic cases of patient dysfunction are treated. Meanwhile, for the effective treatment of heart failure, Ertl et a, 2012) cautioned that leaving out key symptomatic dysfunctions untreated would mean possible cases of reoccurrence of symptoms on patients. Management of side effects and concomitant therapy The results that have been gathered so far has shown that even though there may be major advantages intheuse of combined therapy in patients, there still remains a number of side effects that patients may have to endure in relation to combined therapies. These side effects normally manifest when patients adequately absorb the medical components of one of the therapies in the combined therapy, and then the other therapy may have residual effects on the body which is unused or unabsorbed (Pfeffer and Braunwald, 2000). In such instance, the best approach is to effectively manage the resulting side effect. The most common side effects in combined therapy usually emerge during the early stages of combined therapy. Some of these side effects include hypoperfusion and symptomatic hypotension (The TRACE Study Group, 2004). In these cases, the exclusion of intravascular volume depletion from the treatment is recommended (Ramahi, 2010). Ramahi (2010) suggests that if the side effect is not very severe, adjustments can be made on the time the ACE inhibitor is administered, where it may be taken earlier or later than the beta blocker. Other adjustments include the reduction of the dose of the ACE inhibitor in combined therapy. This would help reduce the severity of the side effects. Where side effects persist, however, absolute discontinuation of the combined therapy is recommended. CONCLUSIONS Summary The current study set out to critically study the efficacy of combined therapy in the treatment of heart failure. This study critically reviewed two combined therapies, namely the combination of ACE inhibitors and beta blockers, and ACE inhibitors and endothelin receptor antagonists. Apart from testing the general efficacy of combined therapy over singular therapy in the treatment of heart failure, the researcher also aimed to find out which of the two combined therapies was more effective in preventing and treating CHF. To achieve the purpose of the study, 20 major literature sources were searched, including a sample for a critical secondary data collection on the two combined therapies. In some cases, single therapies were taken and paired with each other to identify their effectiveness in the treatment of heart failure and other cardiovascular-related diseases. The results of the study showed that in trying to test the efficacy of one of the combined therapies over the other, the efficiency of ACE inhibitors remained the same since it was present in both therapies. The search for efficacy therefore came to rest with the efficiency of beta blockers versus endothelin receptor antagonists. In line with this, the results of treatment of heart failure patients with beta blockers and endothelin receptor antagonists were compared. Based on the comparison undertaken, it was established that combining beta blockers with ACE inhibitors produced more favourable outcomes in most patients suffering from cardiovascular dysfunction. Conclusion and Suggestions for future work Based on the above results and discussion, several conclusions and recommendations have been drawn. First, it can concluded that both ACE inhibitors and beta blockers, and ACE inhibitors and endothelin receptor antagonists produce some level of efficiency in the treatment of heart failure. However, the combined therapy of ACE inhibitors and beta blockers is more preferred, because this seems to be the combination which satisfies many variable conditions of heart failure and cardiovascular dysfunction. Second, inasmuch as the combined use of any of the two therapies have presented favourable therapies for CHF, more in-depth investigations and clinical applications have to be performed on patients with heart failure using the combined therapies before any further recommendations on combined therapies can be made. Third, it is also important for more discerning and clearer patient inclusion and exclusion criteria to be included in future studies in order to avoid errors in the application of combined therapies (The TRACE Study Group, 2004). Finally, there is enough room for further studies to be conducted on this research problem. Suggestions for future research include the conduct of primary research, possibly a randomized controlled trial applying both combination therapies for CHF patients. Through such primary research, more reliable results can be established, including unadulterated findings on the efficacy of combined therapies in the treatment of heart failure. 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(2004), “The Trandolapril Cardiac Evaluation (TRACE) Study: rationale, design, and baseline characteristics of the screened population” Am J Cardiol. Vol. 73 No. 3; pp. 44-50. Van Gilst WH, De Graeff PA, Wesseling H, and Langen CDJ (2006), “Reduction of reperfusion arrhythmias in the ischemic isolated rat heart by angiotensin converting enzyme inhibitors: a comparison of captopril, enalapril, and HOE 498” J Cardiovasc Pharmacol. Vol. 8: No 1, pp. 722-728. Appendix Outcome of Experiment Source: Ramahi (2010). Read More