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The Effect of Neurohormonal Antagonists in Reducing Heart Failure Hospitalizations

Posted on: Thursday, 9 February 2006, 06:00 CST

By Williams, Randall E

Key words: Adrenergic system - Clinical trials - Disease management programs - Heart failure - Hospitalizations - Patient registries - Renin-angiotensin-aldosterone

ABSTRACT

Objective: Heart failure (HF) is a major health problem facing the US and studies suggest that the incidence of this condition will rise significantly over the next 10 years. Limiting the incidence or duration of HF hospitalizations would, therefore, have a major impact on healthcare costs. The purpose of this review is to establish and discuss the proposed neurohormonal mechanisms by which HF can occur along with pharmacologic treatments designed to antagonize these pathological states in order to aid in the reduction of HF hospitalization.

Methods: A Medline search (to December 2004) was performed to compile published literature and assess numerous large-scale studies regarding the use of neurohormonal antagonists in the treatment of HF. In addition, evaluation of statistics and figures from various organizations dedicated to the improvement of HF care was utilized as aids in understanding the impact of these therapies on hospitalization and healthcare.

Results: Heart failure is the most costly cardiovascular disease in the United States, with an estimated annual expenditure in excess of $20 billion. The frequency and duration of HF-associated hospitalizations are the key contributors to this pronounced economic burden. Use of pharmacologic interventions designed to specifically antagonize the renin-angiotensin-aldosterone system and the adrenergic system has had a significant impact on limiting hospitalization with regard to HF. However, the ever burdensome level of re-hospitalization rates for these patients is still problematic and appears to be based on a disconnect between established procedures to effectively treat these patients and the inability to accurately measure performance standards by managed care organization and hospital accreditation bodies. As a consequence, these antagonists, β-blockers in particular, are still underutilized in the treatment of HF. Studies have shown that many of these hospitalizations could have been avoided had healthcare providers followed effective HF management programs.

Conclusions: Current evidence supports the benefits of neurohormonal blockade in decreasing hospital admissions due to HF. Appropriate use of these agents plus agreed-upon guidelines for treatment can continue to significantly decrease total HF-related hospitalizations and costs. Inclusion of β-blockers as a performance measure in quality-of-care HF indicators should be considered as an important instrument to increase their utilization and to improve overall HF care.

Introduction

Heart failure (HF) is a chronic, progressive disease, affecting nearly 5 million Americans, or approximately 2.3% of the general population1, and accounts for over 3.5 million hospital admissions in the United States annually2,3. It is also the most common diagnosis-related group discharge category and the fourth leading cause of adult hospitalizations in the United States4. In patients over 65 years of age, the incidence of HF approaches 10 per 1000 persons1 and is the leading cause of hospitalization in the United States5. Repeat hospitalizations stemming from HF are common, with 40-50% of patients re-admitted within 6 months of initial hospital discharge5.

HF represents a significant financial burden within both the elderly and non-elderly managed care population6. The annual expenditure in the United States is estimated at $27.9 billion for both direct and indirect costs1, which exceeds that of hospitalization for myocardial infarctions and cancers combined2. As the population ages, hospitalizations for HF are projected to increase with improvements in the treatment of coronary artery disease and hypertension4. As both the incidence and prevalence of HF increase with age, care of HF patients will demand an increasing percentage of national healthcare expenditures. Considering that the prevalence of HF is increasing and 550000 new cases were reported last year alone1, sound approaches to preventing and treating this disease are necessary3,7. This article aims to outline an understanding of the neurohormonal mechanisms responsible for HF progression as well as outcomes of trials for the various antagonists of these pathways and their impact on hospitalization. Additional studies are also provided with regard to underutilization of these pharmacological agents, in particular β-blockers, and the need for these agents to be considered as a performance standard for care of the HF patient.

Methods

Relevant articles were identified through a Medline search (to December 2004) using the terms: adrenergic, β-blockers, heart failure, hospitalization, angiotensin receptor antagonists, angiotensin-converting enzyme inhibitor, aldosterone receptor blockade, diuretic, digitalis, clinical trials, costs, neurohormonal antagonists, performance improvement, quality of care, patient registries, disease management programs. Both large clinical trial and community study data on these topics were selected for inclusion. Society information such as that from the American Heart Association and the Heart Failure Society of America was utilized for additional facts and statistics regarding HF.

Supporting the neurohormonal hypothesis

Traditional views of HF have centered around the concept that initial injury of the myocardium allowed for changes in hemodynamic loading conditions (increased preload and afterload), and that over time these stresses exerted deleterious effects on viable (non- injured) myocardium8,9. Physicians, therefore, felt that relief of these hemodynamic stressors, perhaps by vasodilator treatment, would help reduce the progression of HF. This theory was challenged with the first Veterans Affairs Vasodilator-Heart Failure Trial (V- HeFT), in which patients were given oral doses of prazosin, an antagonist to the α^sub 1^-adrenergic receptor, resulting in decreases in blood pressure in order to provide a subsequent reduction in cardiac workload10. However, blood pressure reduction alone with this agent failed to reduce mortality in these patients10. Investigators felt that perhaps this was due to the unopposed α-blockade through prazosin and not due to hemodynamic stressor relief, since use of an alternative set of vasodilators, isosorbide dinitrate and hydralazine, in this study demonstrated a significant reduction in mortality when compared to placebo. Interestingly, within the same time frame that this study was being performed, a new class of drugs was being investigated for their use in blood pressure reduction: angiotensin-converting enzyme inhibitors (ACEIs). The V-HeFT II trial was then designed to compare mortality benefits in HF patients from either isosorbide dinitrate and hydralazine or enalapril, a member of the ACEI class of drugs11. Results from this study demonstrated an added decrease in mortality with use of enalapril, even though use of isosorbide dinitrate and hydralazine demonstrated significantly improved exercise performance and LV function compared to the ACEI11. These sets of results began to challenge the notion that HF progression was mainly a hemodynamic imbalance and point towards a role for the neurohormonal system in the progression of HF. The exact mechanism by which enalapril provided additional benefit in the prevention of mortality was not investigated at the time, but some have speculated that neurohormonal blockade is important in patients receiving diuretic therapy (such as the patients enrolled in the V-HeFT trials) since use of these agents has been shown to cause activation of the neurohormonal system12,13. Use of the loop diuretics has been shown to cause an increase in serum norepinephrine and renin levels12,13. Thus regulation of the renin-angiotensin-aldosterone system in addition to adrenergic regulation (summarized in Figure 1(9,14-16)) has been the main focus in the treatment of HF over the last several years.

Angiotensin-converting enzymes and receptor antagonists

Angiotensin-converting enzyme inhibitors were initially thought to be beneficial due to vasodilation and the subsequent effective decrease in vascular resistance17. The physiological mechanism by which the renin-angiotensin-aldosterone system regulates blood volume has been extensively studied. In response to a drop in blood pressure, sympathetic stimulation, or decreased sodium delivery, the kidney releases renin. Renin is an enzyme that converts angiotensinogen, circulating in the bloodstream, to angiotensin I. This protein then undergoes a second proteolytic cleavage by another enzyme, angiotensin-converting enzyme (ACE), to the final product of angiotensin II (AngII). AngII, acting on the angiotensin receptor, serves as a powerful vasoconstrictor to regulate blood pressure in addition to facilitating cardiac hypertrophy and remodeling with prolonged stimulation (Figure 1)15. Inhibition of the production of AngII or blockade of this ligand's actions on its native receptor has been the focus of many clinical trials aimed at preventing hospitalization due to HF.

Figure 1. Primary neurohormonal pathways affecting heart failure disease progression. CNS, central nervous system.

Sources: References 1, 4, 9, 15, 16

Limiting the levels of circ\ulating angiotensin II by blocking its production through ACEIs has been the focus of several studies in patients with HF. The Studies of Left Ventricular Dysfunction (SOLVD) trial was a double-blind, placebo-controlled study to analyze the effect of a specific ACEI, enalapril, on mortality and hospitalization in patients with reduced left ventricular ejection fraction (LVEF) and congestive HF18. The use of enalapril compared with placebo produced significant risk reductions in overall mortality, HF mortality, and hospitalization in HF patients (16%, 22%, and 26% risk reductions, respectively)18, making a case for its usage in conventional therapy in the treatment of HF patients.

However, use of enalapril for preventing HF hospitalizations has not been shown to be significant in all trials. V-HeFT II compared mortality and hospitalization in patients with congestive HF who were assigned to either enalapril or hydralazine plus isosorbide dinitrate17. Although the use of enalapril did cause a greater reduction in mortality compared with hydralazine/isosorbide dinitrate11, the difference in rate and distribution of times to first hospitalization between the two drugs was not significant17.

Additional members of the ACEI class of drugs have been examined in hospitalization for patients with HF. The placebo-controlled Captopril-Digoxin Multicenter Research Group enrolled 300 patients with mild-to-moderate HF to examine the effects of the ACEI captopril as an alternative to digoxin therapy19. The results of this study showed a significant decrease in the frequency of emergency care of hospitalization for worsening HF (p < 0.05)19. This result further strengthened the place of ACEI therapy in the prevention of future cardiovascular events in HF patients.

In contrast with ACEIs, which limit angiotensin II levels by inhibiting conversion from its inactive form, angiotensin receptor blockers (ARBs) decrease angiotensin activity by antagonizing cell surface receptors. A number of trials have been performed to determine whether this class of drug is beneficial or more beneficial in the prevention of hospitalization. The Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity (CHARM) program was a placebo-controlled study performed to assess the effects of the ARB candesartan on cardiovascular death or hospitalization20. Patients primarily had LVEF ≤ 0.40. The overall CHARM program demonstrated a 16% reduction (p < 0.0001) with candesartan compared to placebo for cardiovascular death or hospitalization in patients with worsening HF20.

The Valsartan Heart Failure Trial (Val-HeFT) enrolled just over 5000 patients with New York Heart Association (NYHA) class II, III, or IV HF21. In this study, use of the ARB valsartan resulted in a significant (p < 0.001) reduction in the number of HF patients hospitalized compared with placebo treatment. This result was felt to be a product of significant improvements in ejection fraction, additional signs and symptoms of HF, and overall quality of life observed with valsartan usage compared with placebo21.

Studies demonstrated that limiting the effects of angiotensin II either by direct reduction in circulating levels (ACEIs) or by preventing their binding to their specific receptors (ARBs) has proven to be important in the reduction of hospitalization for patients with mild-to-severe HF (summarized in Table 1(17-23)). The outcomes of the trials discussed above have led to guideline recommendations24 to limit the effects of angiotensin II in the hopes of improving overall quality of life in these patients.

Aldosterone receptor antagonists

Over the last several years, increasing evidence has been mounting in support of aldosterone, another member in the renin- angiotensin-aldosterone system, as an important mediator of cardiac remodeling in HF. Angiotensin II (described above), acting on the adrenal cortex, causes a release of aldosterone; the role of this hormone in the preservation of sodium-potassium balance has been studied extensively16. However, increased aldosterone levels have been linked to reduced functional capacity in patients with HF25. Many of the effects of aldosterone on HF are entirely non-renal and contribute directly to cardiac remodeling through direct effects on endothelial dysfunction, myocardial apoptosis, and myocardial fibrosis (Figure 1)16. The precise mechanism by which aldosterone contributes to remodeling through these events is not entirely understood and is the focus of many ongoing research projects. Original therapy with ACEIs was felt to be beneficial in limiting the amount of circulating aldosterone by reducing stimulation at the adrenal cortex. However, it has been shown that many patients can 'escape' the relation between angiotensin II and aldosterone in HF26 and additional approaches to limit aldosterone's effects are the focus of many clinical trials.

Table 1. Major ACEI/ARB heart failure trials

Spironolactone, a nonspecific aldosterone receptor antagonist, was one of the first drugs of this family to be used in patients with HF. Original lines of thought regarded ACEI use to be a contraindication to the addition of aldosterone antagonists in the therapy regimen for HF due to an increased risk for serious hyperkalemia. However, early demonstration of tolerance for spironolactone with ACEI treatment led to the Randomized Aldactone Evaluation Study (RALES)27. Of the 1663 patients with severe HF symptoms enrolled in RALES, those treated with low-dose spironolactone showed a significantly decreased risk of progressive HF and sudden death over those patients treated with standard treatment (ACEI, loop diuretic, and digoxin) alone. In addition to the 27% mortality decrease, hospitalization risk was lowered by 35%3,27.

The results of RALES have led to the generation of a more specific mineralocorticoid receptor antagonist, eplerenone28. Eplerenone, up to levels of 100mmol/L, did not inhibit activation of the glucocorticoid receptor or show any agonist activity toward the progesterone receptor, an effect common with spironolactone administration28. Given this specificity, the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) was designed to evaluate the use of eplerenone in post- myocardial infarction patients with complicated left ventricular dysfunction and HF29. The more than 6000 patients in this study were randomized to either placebo or eplerenone in addition to their regular therapy. Use of eplerenone demonstrated a reduced risk for hospitalization due to cardiovascular events (relative risk, 0.87, 95% CI, p = 0.002) in addition to an overall reduction in all-cause hospitalization (relative risk, 0.92, 95% CI, p = 0.02)29. Hyperkalemia was found to increase in patients on eplerenone, but these increases were considered to be manageable29.

Overall, the use of aldosterone antagonists has proven to be beneficial in the reduction of hospitalization for HF patients (summarized in Table 2(27,29)) and, based on the studies reviewed, has been recommended in the treatment of these individuals for improved quality of life24.

β-Blockers

An increase in CNS sympathetic tone has been intimately linked with impaired ventricular function; in addition, patients with high circulating plasma levels of norepinephrine have been shown to have a poor prognosis14,30. Three adrenergic receptors (β^sub 1^, β^sub 2^, α^sub 1^) are primarily responsible for this phenomenon and each plays a unique and significant role in the exacerbation of HF. Prolonged stimulation of all three adrenergic receptors has been linked to ventricular remodeling through either hypertrophy or apoptosis leading to dilation, and in addition contributes to rhythm disturbances within the diseased myocardium (summarized in Figure 1)14. Alterations in rhythmicity can occur via three different possible mechanisms: α^sub 1^-adrenergic receptor activation increases cyclic adenosine monophosphate levels; β^sub 2^-adrenergic receptor activation reduces extracellular potassium concentrations; and α^sub 1^-adrenergic receptor activation triggers potentially arrhythmic after-depolarizations, particularly during myocardial ischemia31. Sympathetic activation through the α^sub 1^-adrenoreceptor at the level of the myocyte has also been shown to have adverse effects on myocardial oxygen delivery, causing further exacerbation of ischemia in the HF patient31. Furthermore, alterations in vascular activity (increased vasoconstriction through α^sub 1^-adrenergic receptor stimulation) and increased sympathetic activity at the level of the kidney can cause significant changes in the renin-angiotensin- aldosterone system (Figure 1)14.

Table 2. Major aldosterone inhibitor heart failure trials

Three β-adrenergic antagonists have been extensively studied in the role of reducing hospitalization in patients with HF: bisoprolol, metoprolol, and carvedilol. While all three drugs are classified as β-blocking agents, there are distinct pharmacological differences between them. Bisoprolol and metoprolol are specific to the β^sub 1^-adrenergic receptor32,33, whereas carvedilol is unique in that it not only antagonizes the β- adrenergic receptor, but also the β^sub 2^-adrenergic receptor and α-adrenergic receptors as well34. Because of its α- blocking actions, carvedilol also acts as a moderate vasodilator on acute administration35. The effect of all three compounds on hospitalization in HF patients is outlined below.

Adrenergic blockade provides additional risk reduction for hospitalization in patients with HF following similar (yet distinct) trends as described with ACEIs, ARBs, and aldosterone receptor inhibitors. In large-scale trials (US Carvedilol Heart Failure Trials, Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure [ME\RIT-HP], Cardiac Insufficiency Bisoprolol Study II [CIBIS-II], and Carvedilol Prospective Randomized Cumulative Survival [COPERNICUS]) the β-blockers carvedilol, metoprolol, and bisoprolol significantly reduced all-cause hospitalizations. In the US Carvedilol Heart Failure Trial Program, 1094 HF patients with LVEF ≤ 35% were randomized to receive carvedilol (n = 696) or placebo (n = 398) in four concurrent protocols36. The majority of patients enrolled in the trial had mild-to-moderate HF, primarily NYHA class II or III. Carvedilol treatment decreased HF progression (48%; p = 0.008), all-cause hospitalization (29%; p = 0.009), cardiovascular hospitalization (28%; p = 0.034), HF hospitalization (38%; p = 0.041), and all-cause mortality (65%; p < 0.001) compared with placebo4,36,37.

Similar results were seen in the CIBIS-II trial (n = 2647) with bisoprolol, which enrolled patients with moderate-to-severe HF symptoms (NYHA functional classes III-IV) with an LVEF ≤ 35%. Treatment with bisoprolol (compared with placebo) in these studies yielded a 20% decrease [p = 0.0006) in the number of all-cause hospitalizations, and further analysis of these hospitalizations yielded a 32% decrease (p < 0.0001) in hospitalizations as a result of worsening HF38.

The MERIT-HF trial evaluated metoprolol CR/XL in 3991 patients with NYHA classes II-IV HF and LVEF ≤ 40%39,40. In this randomized, double-blind, controlled trial, patients who were assigned to metoprolol were initially dosed based on severity of HF with 25mg/day for mild cases and 12.5 mg/day for moderate-to-severe HF with uptitration for 6-8 weeks to a target of 200 mg daily. During the trial period of up to 1 year, use of metoprolol CR/XL significantly reduced all-cause hospitalization (19%, p < 0.001)40.

Most trials involving β-blockers have excluded patients with severe HF, but COPERNICUS is the only β-blocker trial to focus on these patients41. This study evaluated the effects of carvedilol in 2289 patients with LVEF < 25% and stable who were on conventional treatment with ACEIs and diuretics41. Patients treated with carvedilol noted a 24% reduction (p < 0.001) in the combined end point of death or hospitalization compared with placebo, and further analysis of the study population showed that in the high-risk subgroup the decrease was 29% (p = 0.003)41. Among carvediloltreated patients, there was a statistically significant 20% decrease in all- cause hospitalization (p = 0.002), a statistically significant 28% decrease in cardiovascular hospitalization (p = 0.0002), and a statistically significant 33% decrease in hospitalization due to worsening HF (p < 0.0001)42. Further analysis of hospitalization in COPERNICUS showed that patients in the carvedilol group also spent 27% fewer days in the hospital for any reason (p = 0.0005) and 40% fewer days in the hospital for HF (p < 0.0001)42. Based on the data from this trial, carvedilol appears to reduce HF hospitalizations in mild, moderate, and severe cases4,43.

Figure 2. Multicenter Oral Carvedilol Heart Failure Assessment (MOCHA): dose-response effect of carvedilol treatment on mortality and morbidity. Patients (placebo, n = 84; carvedilol, n = 261) received diuretics, angiotensin-converting enzyme inhibitors, and/ or digoxin for 6 months of follow-up. Adapted from Bristow et al.46, with permission

When compared to placebo, β-blocker use demonstrates significant benefits in the reduction of HF hospitalizations. The Carvedilol or Metoprolol European Trial (COMET) was a head-to-head comparison of the benefits of metoprolol tartrate and carvedilol treatment in 3029 NYHA HF class II and III patients44. After a 58- month follow-up period, they found an 11% lower risk of all-cause mortality or HF hospitalization (p = 0.019) and a 9% lower risk of all-cause mortality or worsening HF (p = 0.046) with carvedilol compared with metoprolol tartrate use45. There was a significantly lowered annual all-cause mortality rate for carvedilol compared with metoprolol tartrate (8.3% vs. 10.0%, respectively, p = 0.0017). Carvedilol also extended median survival time by 1.4 years44. Some critics have challenged the results of this study on the basis that the formulation of metoprolol used in COMET (metoprolol tartrate) was not the same formulation shown to be beneficial in the MERIT-HF studies (metoprolol succinate).

The question has been raised of whether a dose that is considered less than optimal will decrease hospitalizations and mortality. If a patient is unable to tolerate the maximum dose of a β-blocker, will they still benefit from therapy? The value of all doses of β-blockers was shown in the Multicenter Oral Carvedilol Heart Failure Assessment (MOCHA) trial46, a multicenter, placebo- controlled trial in which 345 patients with mild-to-moderate HF were randomized to receive either placebo or low (6.25 mg bid), medium (12.5 mg bid), or high (25 mg bid) doses of carvedilol. Although there was a dose-related improvement in LVEF (p < 0.01), the rates of hospitalization were statistically significant from placebo (p = 0.01) but were not dose-related (Figure 2)46. The rates of hospitalization for the lowest dose (6.25 mg bid) were statistically similar to the highest dose (25 mg bid) in preventing hospitalization rates for patients taking carvedilol.

In addition to investigations of hospitalization rates, a retrospective study of medical insurance claims submitted by HF patients was performed to investigate the use of carvedilol and metoprolol (formulation in this study was unspecified) to reduce hospitalizations47. In this study, all-cause hospitalizations were significantly lower in carvedilol-treated patients than in metoprolol-treated patients (36.0% vs. 62.3%, respectively, p < 0.001). Emergency room visits were also significantly lower in the carvedilol-treated group (23.7% vs. 42.5%, p = 0.002). The investigators concluded that the more comprehensive adrenergic blockade provided by carvedilol, a nonselective β^sub 1^/ β^sub 2^/α^sub 1^-blocker in contrast to the β^sub 1^- selective blocker metoprolol, may have accounted for its greater clinical benefits47.

The clinical trials utilizing β-adrenergic antagonists provide strong evidence for their inclusion as a means of therapy for patients with moderate-to-severe HF. Use of β-blockers has proven to reduce hospitalizations (summarized in Table 3(36,38,39,41,42,44)), showing them to be cost-effective for healthcare over time.

Neurohormonal antagonists as performance indicators

Although many clinical trials support the use of neurohormonal antagonists to treat HF, these agents, β-blockers for example, are inadequately administered48. The general lack of knowledge about their benefits along with concerns that these agents may induce cardiac decompensation, even in patients with mild HF, prevent them from being widely used49. Some physician reluctance in prescribing β-blockers may also be due to the idea that these medications require close monitoring and attention.

Table 3. Major β-blocker heart failure trials

For in-hospital and outpatient settings, comprehensive performance standards should include HF treatments proven effective to decrease HF hospitalizations. This is currently the case for the use of ACEIs, which are incorporated into most HF core measure sets. However, not all guidelines for the management of HF include β- blockers in their medication quality indicators. For example, the Core Measure Set for JCAHO only recommends ACEIs for LVSD50. Based on the evidence presented above, by mandating the use of evidence- based β-blockers for the treatment of HF, health plans and managed care organizations could substantially reduce mortality, subsequent hospitalizations, and overall economic burden associated with its disease progression. Despite supporting evidence of their benefit in HF, β-blockers are not part of Medicare's Quality Improvement Organization program. By including β-blockers for the treatment of HF, improved care and outcomes in hospitalized HF patients will occur much in the same way that they did by including ACE inhibitors for both acute myocardial infarction and HF51.

The hospital is an important healthcare setting to consider for implementing programs aimed at improving quality of patient care and utilizing evidence-based, guideline-recommended treatments52. Numerous lines of evidence support the rationale for a hospital- based quality of care program for HF. Medical therapy for HF may be more likely to be initiated by physicians who routinely treat HF patients and in a setting where they can rapidly get the necessary support and resources (multidisciplinary care team, protocols, critical pathways, tests, procedures) to administer therapy in an efficient way51,53. Studies have demonstrated that cardiovascular medications are more likely to be continued by physicians in the outpatient setting when initiated in the hospital52. Patients are also more likely to view these medications as essential, and to adhere to treatment (lower discontinuation rates) as well as achieve treatment goals, when these therapies are started in the hospital52. An analysis of acute myocardial infarction treatments showed that patient education, such as counseling for smoking cessation, has been demonstrated to be more effective when initiated in the inpatient setting as opposed to delaying until after the patient has been discharged34 and one could easily apply these same theories to patients with HF.

The tolerability and utilization of β-blockade initiation prior to hospital discharge was recently studied in the Initiation Management Predischarge: Process for Assessment of Carvedilol Therapy for Heart Failure (IMPACT-HF) trial55. Patients hospitalized for HF (n = 363) were randomized either to carvedilol initiation prior to discharge or to in\itiation of any β-blocker at physician discretion at least 2 weeks after discharge ('usual care'). At 60-day follow-up, 91% of the carvedilol predischarge initiation group was receiving β-blocker therapy compared with 73% of the usual-care group (p < 0.0001). The carvedilol predischarge initiation group had fewer withdrawals for worsening HF, and the length of hospital stay was not increased55. In addition, a trend towards a lower rate of re-hospitalization was observed with the carvedilol predischarge group. This study provides strong evidence in support of the inclusion of β-blocker therapy as a core HF performance indicator, and β-blocker initiation prior to patient discharge proves to be the best course of action in improving rates of re-hospitalization. Further evidence supporting early benefits from β-blocker use has been demonstrated by the analyses of the COPERNICUS database, which showed that the benefits of carvedilol treatment occur early in the treatment period43. Carvedilol treatment resulted in improved mortality and re-hospitalization rates within the initial 8 weeks of therapy43.

The economic impact of β-blocker use has been analyzed and has shown that the incremental expected cost per year of life saved is $3300 for bisoprolol, $2500 for metoprolol, and $6700 for carvedilol56. Further analysis of β-blocker use demonstrated that these beneficial medications demonstrated significant decreases in per-patient length of stay and hospitalization costs, and thus an even greater impact on healthcare costs4. Specifically, the inclusion of carvedilol in treatment programs cut the mean per- patient cost of hospitalization by more than half for cardiovascular admissions and reduced it by 81% for HF admissions4. Furthermore, a retrospective cost analysis of health insurance claims data from a propensity-matched sample of patients revealed that expected costs of inpatient care were as much as $10500 lower for treatment with carvedilol than for treatment with metoprolol tartrate at 36 months57. This cost analysis suggests that differences between carvedilol and metoprolol tartrate therapy may in fact be more beneficial long term and offset the significantly higher pharmacy costs that have been associated with carvedilol compared with metoprolol (mean $1677 vs. $1322 over a 6-month period; p < 0.001)47.

Given the evidence presented regarding the use of β- blockers and their long-term benefits in reducing hospitalizations, along with associated costs, the limited use of β-blocker in the treatment of HF patients should be viewed as a concern, and approaches are needed to provide an adequate message to both physicians and patients about their importance. Furthermore, these approaches and concerns can be applied to all neurohormonal antagonists, which are recommended by various societies in the treatment of HF.

Improving HF care through registry-based programs

Although clinical trials are the gold standard in determining the efficacy of a drug, some feel that, while these studies are a good first step, more analysis needs to be performed regarding the effectiveness of a drug in a non-controlled environment. These concerns are beginning to be evaluated with the use of registry- based programs. One specific registry-based program for evaluation of neurohormonal approaches is The Coreg Heart Failure Registry (COHERE)58. This registry followed 4280 patients with HF on carvedilol 6.25 mg to 25/50 mg bid (based on weight) for a mean of 12 months at 388 community practices. This registry demonstrated that hospitalizations decreased dramatically after 12 months of carvedilol treatment compared with the 12 months prior to treatment (Figure 3)58. This result confirmed what controlled clinical trials demonstrated; carvedilol usage significantly reduced hospitalization in HF patients.

Currently, another patient registry program in place is designed with a broader goal in mind. The Organized Program To Initiate Life- Saving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF) is a national program that aims to improve outcomes in patients hospitalized for HF by implementing evidence-based, guideline-driven HF management practices, including the use of β-blockers59. This program is a web-based registry and process- of-care intervention map that will not only collect data regarding hospitalizations, but also provide information regarding best practices for in-hospital management of HF as well as patient- education materials59. The OPTIMIZE-HF initiative should provide further information on the effects of β-blocker use in hospitalized HF patients, during both the hospitalization period and short-term (60- to 90-day) follow-up. A preliminary data analysis showed that the majority of patients discharged from the hospital on β-blockers tolerated therapy and highlighted the fact that those not discharged on therapy remained untreated during the 60- to 90-day follow-up period. Interestingly, more patients discharged on β-blockers had remained committed to their drug regimen compared with those patients discharged on ACEIs/ARBs alone (95.2% vs. 73.4%; p < 0.0001)60.

Figure 3. The Coreg Heart Failure Registry (COHERE): hospitalizations 12 months prior to and 12 months after carvedilol treatment. In this study, 4280 patients with HF on carvedilol 6.25- 25/50 mg bid (based on weight] were followed for a mean of 12 months at 388 community practices (259 cardiologists, 129 primary care physicians). Adapted from Franciosa et al.58, with permission

Disease management programs: another avenue for improving HF quality-of-care

The structured framework of disease management programs for HF has also been associated with increased utilization and administration of neurohormonal antagonists61. By increasing adherence to professional guidelines on standard HF treatments, disease management programs have been shown to reduce hospitalization rates and improve clinical outcomes61.

In a systematic review, McAlister et al.62 reported that HF disease management programs have had beneficial effects on physician prescribing practices. In the randomized trials analyzed, disease management programs were associated with significantly greater use of therapies proven to be effective in the treatment of HF62. One specific comprehensive HF disease management program between 1991 and 1994 included 214 patients in NYHA class III or IV HF for at least 6 months prior to referral63. All patients at the time of study had a detailed history taken, underwent physical assessments of cardiac performance, and were given a comprehensive educational primer as to their health and all interventional steps taken to improve their quality of life. The program initiated changes in medication regimen that resulted in a 98% increase in ACEI dose and a flexible diuretic dosing regimen 6 months after program initiation. Furthermore, significant improvements in functional status (p < 0.001) were observed, including decreased pulmonary artery wedge pressure and decreased systemic vascular resistance63. As a result of these improvements, significant decreases in hospital admission rates (p < 0.0001) over the evaluation period were also noted for these patients63.

A multidisciplinary treatment strategy has been shown to improve medication compliance in the HF patient, particularly the elderly HF patient, leading to improved outcomes. For example, Rich et al.64 examined 156 patients > 70 years of age assigned to either conventional care (n = 76) or multidisciplinary care (n = 80) consisting of comprehensive patient education, dietary and social service consultations, medication review, and intensive post- discharge follow-up. Medication compliance, as measured 30 days after discharge, was significantly greater in the multidisciplinary care group than in the conventional care group (88% vs. 81%, p = 0.003). Patients assigned to multidisciplinary care were also less likely to be readmitted to the hospital and stayed in the hospital for a fewer number of days, if readmitted, than those in the conventional care group (32.6% and 30.7% reductions, respectively; p = NS). Based on the data obtained in this study, a multidisciplinary approach significantly increased compliance, which may have contributed to improved clinical outcomes in patients with HF64.

Figure 4. Percentage of patients with ft-blocker initiation or uptitration by randomized group. For each outcome, more patients were: initiated or uptitrated on $-blockers, initiated on $- blockers, and at target doses at the end of the study with the nurse facilitator treatment (p < 0.001). Adapted from Ansari et al.65, with permission

This strategy was further confirmed in a recent study by Ansari et al.65, who found that nurse facilitators were an important component of the successful implementation of a β-blocker guideline in HF patients. A randomized controlled trial involving 169 HF patients was designed to test the importance of an educational approach through nurse facilitators in teaching patients the importance of β-blocker adherence. The study was organized into three groups: (1) the control group, in which patients were provided only education from the provider regarding β-blocker usage on their initial visit; (2) the provider and patient notification group, where a computerized reminder from the provider was administered along with patient letters that advocated β- blocker adherence; and (3) the nurse facilitator group, in which a supervised nurse practitioner was utilized to initiate and monitor β-blocker use65. The investigators found that the proportion of patients on target β-blocker doses after a 12-month period was highest in the nurse facilitator group (43%) compared with the control group (10%, provider education only) and provider/patient notification group (2%; p < 0.001). There were n\o differences in adverse events among the three groups (Figure 4)65. The use of a nurse facilitator was proven to be a successful approach in the implementation and continuation of β-blockers for the HF patient and perhaps this concept could be translated into adherence for all recommended neurohormonal antagonists in HF guidelines.

Conclusions

HF-related hospitalizations account for much of the cost associated with this chronic disease. The number of patients with HF is expected to rise given recent improvements in treatments and the aging of the population; consequently, HF hospitalizations are expected to increase as well. Several large-scale, randomized, placebo-controlled trials have shown that neurohormonal antagonism, particularly ACE inhibition, adrenergic blockade, and aldosterone antagonism, has beneficial clinical outcomes and effectively reduces hospitalization rates in patients with HF. Both ACEIs and β- blockers are recommended by current professional society guidelines, but studies show that these antagonists are still underutilized. Specific approaches taken to evaluate effectiveness and maintain medication adherence in a real clinical setting have been demonstrated with β-blocker usage, and these principles and practices could easily be applied to additional neurohormonal antagonists. Adopting these care standards could help to improve the quality of HF care, save lives, and decrease the overwhelming rate of hospitalizations and associated costs stemming from HF.

Acknowledgment

This paper was supported by a technical grant from GlaxoSmithKline, Philadelphia, PA, with editorial support provided by Accel Health, New York, NY.

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Randall E. Williams

Evanston Northwestern Healthcare, Northwestern University, Chicago, IL, USA

Address for correspondence: Randall E. Williams, MD, FACC, Midwest Heart Specialists, 1585 North Barrington Road, Suite 302, Hoffman Estates, IL 60194, USA. Tel: +1 847 881 8704; Fax: +1 847 570 1954; email: rwilliams@northwestern.edu

Copyright Librapharm Jan 2006

Source: Current Medical Research and Opinion

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