Do beta adrenoceptor blocking agents provide the same degree of clinically convincing morbidity and mortality benefits in patients with chronic heart failure? A literature review

Chronic heart has been extensively characterized as a disorder arising from a complex interaction between impaired ventricular performance and neurohormonal activation [1]. Activation of the sympathetic in patients with chronic heart failure [2]. Levels of circulating catecholamine’s increase in patients with heart failure which; and those with the highest plasma levels of norepinephrine have the most unfavorable prognosis [3]. Sympathetic activation is a signi icant predictor of poor prognosis in patients with chronic heart failure. There is an overwhelming evidence that supports the notion that, drugs interfering with the neurohormonal activation (including sympathetic activation) in chronic heart failure Abstract


Introduction
Chronic heart has been extensively characterized as a disorder arising from a complex interaction between impaired ventricular performance and neurohormonal activation [1]. Activation of the sympathetic in patients with chronic heart failure [2]. Levels of circulating catecholamine's increase in patients with heart failure which; and those with the highest plasma levels of norepinephrine have the most unfavorable prognosis [3]. Sympathetic activation is a signi icant predictor of poor prognosis in patients with chronic heart failure. There is an overwhelming evidence that supports the notion that, drugs interfering with the neurohormonal activation (including sympathetic activation) in chronic heart failure Abstract Chronic heart failure has been extensively characterized as a disorder arising from a complex interaction between impaired ventricular performance and neurohormonal activation. Since beta adrenoceptor blocking agents are currently considered an integral component of therapy for the management of patients with severe chronic heart failure; several well designed clinical trials have been conducted to determine the morbidity and mortality benefi ts of these agents these studies, however did not yield the same results in terms of morbidity and mortality benefi ts. Currently only Bisoprolol, Carvedilol and sustained release metoprolol succinate have clinically proven and convincing morbidity and mortality benefi ts the current list of approved medicines of the National Health Insurance Scheme (NHIS) of the republic of Ghana does not provide coverage for these lifesaving therapeutic agents. The objective of this review was to collate the relevant scientifi c evidence that will convince the authorities at the National Health Insurance Authority (NHIA) of the Republic of Ghana to include at least one of the evidence based beta adrenoceptor blocking agents in the list of approved medicines.
A thorough search on the internet was conducted using Google scholar to obtain only the clinically relevant studies associated with the benefi ts of beta adrenoceptor blocking agents in patients with chronic heart failure published in the English language. The phrases beta adrenoceptor blocking agents and chronic heart failure were used as search engines.
The search engine yielded several studies that met the predefi ned inclusion criteria. However, only the Cardiac Insuffi ciency BIsoprolol Studies (CIBIS-I and CIBIS-II), Carvedilol Prospective Randomized Cumulative Survival Study (COPERNICUS) and Metoprolol CR/XL Randomized Intervention Trial (MERIF-HF) because of the clinical relevance of their fi ndings Beta adrenoceptor blocking agents such as atenolol and propranolol have been used in the management of patients with chronic heart failure. However, their effi cacy and optimal dose in reducing mortality have not been scientifi cally established not all beta adrenoceptor blocking agents scientifi cally studied provide the same degree of clinically meaningful and convincing morbidity and mortality benefi ts in patients with chronic heart failure. not only produce symptomatic relief; but are also capable of attenuating disease progression, with concomitant reductions in both morbidity and mortality [4].
Beta adrenoceptor blocking agents which antagonize the effects of the activated sympathetic nervous system have been shown to be bene icial in the long term in moderate to severe chronic heart failure in terms of signi icant improvements in both morbidity and mortality [5][6][7]. Several well designed clinical trials have been conducted to determine the bene icial effects of beta adrenoceptor blocking agents on morbidity and mortality in chronic heart failure patients [8].

Objectives of the Review
To research and document the available scienti ic evidence that supports the use and bene its of the evidence-based beta adrenoceptor blocking agents in chronic heart failure. Present the data coupled with pertinent recommendations to the relevant authorities at the National Health Insurance Authority (NHIA) of the republic of Ghana for consideration and possible inclusion into the medicines list of the NHIS.

Scope of the review
This review was focused mainly on the use and bene its of beta adrenoceptor blocking agents in the management of patients with chronic heart failure only; since the bene its of these agents in the setting of acute Decompensated heart failure is still somehow of a therapeutic controversy and very much constitutes a clinical conundrum for most practicing clinicians.
Emphasis was also placed only on the studies associated with carvedilol, bisoprolol and metoprolol succinate which have the most clinically convincing and meaningful morbidity and mortality bene its in patients with chronic heart failure. A metanalysis or systematic review was beyond the scope of this scienti ic activity.

Motivation for the review
Despite the overwhelmingly convincing scienti ic evidence supporting the use and bene its of Carvedilol, Bisoprolol and sustained release Metoprolol succinate in the management of patients with heart failure; the medicines list of the National Health Insurance Scheme (NHIS) of the republic of Ghana does not provide coverage for these lifesaving therapeutic agents. Instead, only atenolol and propranolol are covered which do not possess the necessary scienti ic evidence to justify their use and bene its in the management of patients with chronic heart failure.

Pathophysiological background of beta adrenoceptor blocking agents use in clinical practice
Beta adrenoceptor blocking agents are competitive antagonists that block the binding of epinephrine on beta adrenoceptors of the sympathetic nervous system which mediates the ight or light response [9]. There are two main types of beta adrenoceptors of physiological and clinical relevance namely: Beta-1 adrenoceptor and beta-2 adrenoceptor. Beta-1 adrenoceptors are located mainly in the heart and in the kidneys, while beta-2 adrenoceptors are distributed within vascular smooth muscles, lungs, Gastrointestinal tract, liver and uterus [10]. Increased Sympathetic nervous system activity by epinephrine causes the release of other stress hormones such as cortisol which can potentially precipitate diseases such as heart failure, Angina and cardiac arrhythmias. Beta adrenoceptor blocking agents antagonize the effects of epinephrine at beta-1 adrenoceptor sites especially within the myocardium, hence preventing the development of ischemic heart disease [11].

Summary of therapeutic benefi ts of beta adrenoceptor blocking agents in chronic heart failure
Beta adrenoceptor blocking agents exert several bene icial effects in patients with chronic heart failure including, reversal of cardiac modeling, anti-ischemic effects, metabolic bene its, inhibition of apoptosis and improving both systolic as well as diastolic functions [7,8] (Table 1 and Figure 1).

Summary of scientifi c evidence associated with the benefi ts of beta adrenoceptor blocking agents in heart failure
Several clinical trials have demonstrated a remarkable consistency with regards to an improvement of left ventricular ejection fraction during chronic use of beta adrenoceptor blocking agents [9]. This improvement in ventricular function Table 1: Summary of the different benefi ts of beta adrenoceptor agents in heart failure.

Serial Numbers
Types of benefi ts of beta adrenoceptor blocking agents in heart failure   is due to increased systolic ventricular performance. The same studies have also shown that beta adrenoceptor blocking agents can produce both hemodynamic as well as symptomatic improvements in chronic heart failure patients. Based on the knowledge about these Physiological and clinical effects of beta adrenoceptor blocking agents in patients with chronic heart failure, numerous clinical studies have been conducted to demonstrate the overall cardiovascular morbidity and mortality bene its of these therapeutic agents (Table 2).
Meta-analysis of beta adrenoceptor blocking agents trials have shown a reduction in mortality of approximately 30-35% [10]. The beta adrenoceptor blocking agents that have been studied for chronic heart failure and have demonstrated a reduction in mortality include bisoprolol, carvedilol and sustained release metoprolol succinate (Hence these agents are routinely referred to as evidence-based beta adrenoceptor blocking agents).
It is unknown whether other beta adrenoceptor blocking agents such as atenolol and propranolol have similar bene icial effects ,since not all studied beta adrenoceptor blocking agents have shown clear and clinically convincing reduction in mortality.
Carvedilol has been shown to decrease mortality in patients with NYHA Class II-IV Heart failure (COPERNICUS/US CARVEDILOL STUDY) [14,15]. Sustained release metoprolol succinate has primarily been studied in patients with NYHA Class II-III with a reduction in morbidity and mortality (MERIT-HF) [16]. Bisoprolol has also been studied in patients with NYHA Class II-IV Heart failure and has been shown to reduce morbidity and mortality (CIBIS) [17,18].
The bene its of beta adrenoceptor blocking agents in patients with chronic heart failure were previously considered to be as a result of a class effect; meaning all these agents are equally effective at equipotent doses. However, the Carvedilol or Metoprolol European Trial (COMET) [19] has shown that in patients with chronic heart failure; survival appears to be better with carvedilol than with immediate release metoprolol tartate. Carvedilol was used at a dose of 25mg orally twice daily while immediate release metoprolol tartate was dosed at 50mg twice daily.

Clinical commentary based on recommendations from current heart failure clinical practice guidelines
In order to provide the best care for patients with severe chronic heart failure , clinicians must go beyond the conventional ACE Inhibitor plus diuretic therapies.Adding one of the three evidence based beta adrenoceptor blocking agents at recommended doses will further improve the survival rates and decrease hospitalization rates.

Other non-Heart Failure indications of beta adrenoceptor blocking agents in clinical Practice
Beta adrenoceptor blocking agents constitute a category of therapeutic agents that are very safe and effective in the Pharmacological management of a variety of cardiovascular system disorders such as heart failure, cardiac arrhythmias, angina Pectoris, myocardial infarction and hypertension because of their anti-ischemic, anti-arrhythmic and antihypertensive properties [21]. Their general mechanism of action is derived from competitively binding to beta adrenoceptors during activation of the sympathetic nervous system.

Therapeutic bene its of beta adrenoceptor blocking agents in Hypertension:
Beta adrenoceptor blocking agents were previously considered as irst line option for the treatment of hypertension. However, recent scienti ic evidences suggest that they are no longer preferred irst choice for the initial management of hypertension in most patients [22]. In daily clinical practice, it is acceptable to use Therapeutic bene its of beta adrenoceptor blocking agents in Cardiac arrhythmias: The anti-arrhythmic effects of beta adrenoceptor blocking agents are generally as a result of their direct cardiac electrophysiological actions that include: reduced heart rate, decreased spontaneous ectopic pacemakers, slowed conduction and increased refractory period of the Atrioventricular (AV) node [23,24].
Therapeutic bene its of beta adrenoceptor blocking agents in myocardial Infarction: The mechanisms of actions of beta adrenoceptor blocking agents in the management of myocardial infarctions are associated with a reduction of the sympathetic drive and myocardial ischemia, improvement of barore lex function, inhibition of cardiac apoptosis mediated via activation of the beta adrenergic pathways, inhibition of platelet aggregation, reduction of the mechanical stress imposed on the plaque, preventing plaque rupture, resensitization of the beta adrenergic pathways and changes in myocardial gene expression [24].
Therapeutic bene its of beta adrenoceptor blocking agents in Angina Pectoris: Beta adrenoceptor blocking agents are very useful medications in the management of the different types of angina pectoris, except for Prinzmetal's Angina where they constitute a contraindication. The therapeutic effects of beta adrenoceptor blocking agents in patients with stable angina pectoris can be attributed to their ability to inhibit beta-1 adrenoceptor mediated stimulation of the heart rate and myocardial contractility, resulting in an improved oxygen supply -demand balance within the myocardium [25].

Conclusion
Although therapy with beta adrenoceptor blocking agents constitute an integral part of the standard of care for the management of patients with chronic heart failure; not all these agents have proven morbidity and mortality bene its.
Beta adrenoceptor blocking agents such as atenolol and propranolol have been routinely used in the management of patients with chronic heart failure. However, their ef icacy and optimal dose in reducing morbidity and mortality have not been scienti ically established.
Several well designed and conducted clinical trials have demonstrated convincingly the bene icial effects of the evidenced based beta adrenoceptor blocking agents on morbidity and mortality in chronic heart failure patients. Hence these agents are duly included in several national and international clinical practice guidelines.
Based on the overwhelming cardiovascular morbidity and mortality bene its of these evidence based beta adrenoceptor blocking agents in the management of patients with chronic heart failure; most developed and developing countries have included them in their respective national drug formulary. Carvedilol is preferred over immediate release metoprolol tartate. Beta adrenoceptor blocking agents are also used in daily clinical practice to manage several non heart failure diseases such as angina pectoris, cardiac arrhythmias and myocardial infarction.

Practice implications
The unavailability of the evidence-based beta adrenoceptor blocking agents on the medication formulary of the NHIS, has compelled most practicing clinicians to manage their chronic heart failure patients with beta adrenoceptor blocking agents such as atenolol and propranolol which have no scienti ic evidence at all to justify their use and bene its in this subset of patient population. However, a handful of clinicians with a better appreciation for the principles of evidence-based medicine will still prescribe one of these evidence-based beta adrenoceptor blocking agents, mostly carvedilol for their patients to be purchased out of pocket.
Those patients who cannot afford to purchase the evidence based beta adrenoceptor blocking agents out of pocket as well as those who are receiving therapy with the non evidence based agents are all excellent candidates for poor prognosis and increase risk of cardiovascular morbidity and mortality.

Recommendations to the NHIA for Consideration
 Since the scienti ic evidence supporting the use and bene its of the evidence-based beta adrenoceptor blocking agents in the management of patients with chronic heart failure is so clinically convincing authorities at the NHIA of the Republic of Ghana should consider including at least one of these agents preferably carvedilol in the formulary of approved medications  Atenolol should be maintained but propranolol should be deleted permanently  Clinicians must be encourage to prescribe these agents with prudence keeping in mind the dosing requirements as stipulated in the current clinical practice guidelines in order to maximize therapeutic outcomes for all patients  Decision makers at the NHIA should also ensure that recommended formulary changes should involve all relevant stakeholders in order to allow for smooth transition and implementation  All experts engaged by the NHIA to clinically vet all submitted claims must keep a microscopic eye on the appropriate use of these evidence based agents in the management of patients with chronic heart failure so as to improve therapeutic outcomes