Overview of ACC/AHA Guidelines for Chronic Heart Failure

Sharon A. Hunt
Stanford University, Stanford, CA

Heart failure is a major public health issue, with 5 million people in the US and an estimated 22 million worldwide with heart failure. The annual death rate for heart failure is 300,000. Heart failure is the only cardiovascular (CV) diagnosis that is increasing. An enormous population of older people with heart failure is being created, because of the aging of the population and increasingly effective therapies that prolong life for people with heart failure. Sudden cardiac death is also being prevented in these patients, increasing the size of the population requiring management.

A major message from the guidelines is that there is a large body of evidence showing that heart failure can be prevented or at least delayed, by a number of modalities. In the US and worldwide, what is known to be effective is underutilized. A plea for the more effective use of the evidence base is a major thrust of the updated guidelines.

The ACC/AHA guidelines address only chronic heart failure and heart failure in the adult. The treatment of acute heart failure merits its own set of guidelines. All of the major trials and hence the evidence-base is in adults and there is little real evidence-base in the pediatric population. In general, the causes of pediatric heart failure are different.

Stages of heart failure

Heart failure is viewed as a set of stages. Stage A is persons at high risk for the development of heart failure. This is to promote awareness of the large number of people at high risk and effective therapies to prevent heart failure. Stage B is persons with asymptomatic left ventricular dysfunction (ASVD), and who are usually discovered to have this condition and are at risk for clinical heart failure. Stage C is persons with past or current symptomatic heart failure. Stage D is persons with end-stage heart failure who are dying from heart failure.

Importantly, the four stages in the ACC/AHA guidelines do not replace the NYHA classes of heart failure, but are intended to complement the guidelines. The stages progress inexorably from Stage A to Stage D, whereas movement within the NYHA classes can be in both directions. The stages are specifically designed to emphasize that heart failure is preventable, with emphasis on identification and treatment to prevent heart failure.

Therapy by stages

Stage A therapy consists of treatment of the specific risk factors in a patients, such as hypertension, diabetes, dyslipidemia, ASVD, and controlling conditions that may cause cardiac injury.

Stage B therapy is the treatment of risk factors and the use of ACE inhibitors to delay the onset of heart failure and improve survival. Whether the addition of beta blockers in this asymptomatic group will have similar salutory effects is not known as it has never been studied in a clinical trial. The consensus, despite the lack of evidence, is that beta blockers are a reasonable addition and they probably should be given as tolerated to patients with ASVD.

Active screening of the population for ASVD has not been the subject of a clinical trial and is unresolved. Although the panel consensus is that active screening would be productive, there is no consensus within the profession on the advisability of such an expenditure. Screening would probably need to be restricted to a high-risk population because of expense.

Stage C outlines the evidence-based therapies. The treatment of underlying risk factors and other preventive measures should be undertaken. Drugs to avoid in these patients include most antiarrhythmic agents with the notable exception of amiodarone, most calcium antagonists with the exceptions of amlodipine and felodipine, and NSAIDs, which can exacerbate the clinical syndrome.

Multiple drug therapies are required. However, many of these modalities are grossly underutilized, perhaps in part because of their complexity. Drugs recommended for routine use in virtually all patients are the Ûgbig fourÛh: diuretics, ACE inhibitors, beta blockers, digitalis. Importantly, practitioners should use the specific agents that have been proven in the clinical trials, and not assume class effects for all drugs, and they should aim for the actual doses proven to be effective in the trials. Drugs that should be considered in subsets of patients with heart failure include the 1) aldosterone antagonists, 2) angiotensin receptor blockers as alternatives to ACE inhibitors in specific patients, 3) the combination of hydralazine and nitrates, and 4) exercise training, which has been shown to improve quality of life.

Drugs and interventions of unproven benefit, that are popular in the therapy of heart failure, include nutritional supplements, hormonal therapies, intermittent intravenous inotropes, and cardiomyoplasty, which is used little now.

Stage D therapy includes all therapies used for Stages A through C. For patients who are truly end-stage, practitioners often face the difficult decision of whether to identify them as part of group of patients who should receive aggressive therapy and offer mechanical and surgical strategies, or attempt to provide compassionate end-of-life care. For the vast majority of patients dying of heart failure, compassionate end-of-life care is the most appropriate and is often not carried out well by cardiologists, and much can be learned from oncologists.

Cardiac transplantation is the most tried and true aggressive intervention. It provides an excellent survival rate and quality of life, but quantitatively is a small contribution to the number of deaths from heart failure. Much is written and discussed about high-risk surgery for these patients, include mitral valve repair, surgical remodeling of left ventricle, and most recently on the horizon is the potential use of permanent mechanical circulatory support.

Beta-Adrenergic Receptor Blockade in CHF: A Rational Tool for the 21st Century

Tsutomu Yoshikawa
Keio University School of Medicine, Tokyo, Japan

Congestive heart failure is characterized by activation of the sympathoadrenal and renin-angiotensin systems. The sympathoadrenal system is essential to maintain the circulatory system in the face of stress. However, activation of this system over time has been shown to adversely effect the pathophysiology via multiple mechanisms, such as cardiac hypertrophy, oxygen free radicals, proinflammatory cytokines, matrix matalloproteinase, in addition to the classic concept of energy expenditure through increased oxygen consumption.

The adverse effect of protracted sympathoadrenal activation was recently shown by data from transgenic mice overexpressing beta-1 adrenergic receptors. The mice initially exhibited hypercontractility, but eventually cardiac hypertrophy and failure, resulting in premature death.

Large-scale clinical trials with carvedilol, bisoprolol, and metoprolol have demonstrated that beta-blockers (BB) improved survival in patients with mild to moderate heart failure.

Carvedilol was shown effective in advanced heart failure in the COPERNICUS trial, and it reduced total mortality by 65% in the US Carvedilol Heart Failure Study. There are few data on clinical trials in the Japanese heart failure population. Yoshikawa and colleagues showed in a randomized, placebo-controlled clinical trial that carvedilol significantly reduced CV events compared to placebo. Notably, even low dose carvedilol (5 mg daily) was beneficial in preventing CV events in this population.

However, echocardiographic left ventricular ejection fraction (LVEF) was higher in the high-dose versus the low-dose group at the end of study, showing a dose-response to carvedilol for left ventricular function (Figure 1). The MOCHA trial demonstrated a dose-dependent decrease in mortality with carvedilol. Hence, BB should be uptitrated to the maximum dose, if tolerated, although low-dose BB are useful in preventing CV events.

Are there differences between the first-generation BB such as metoprolol and third-generation BB such as carvedilol? Yoshikawa and colleagues propose that agonism and the antiadrenergic effect are the critical pharmacologic profile in this regard. BB have been thought to compete with intrinsic norepinephrine against uniform beta-adrenergic receptors. However, recent findings from transgenic mice suggested there are 2 forms of receptors, active and inactive in the absence of endogenous norepinephrine, which is referred to as Ûginverse agonism.Ûh Because BB with such inverse agonism transforms active receptors to inactive receptors, in the milieu of low sympathetic activity, adverse cardiac events including worsening heart failure will occur during the titration period.

These investigators showed that metoprolol dose-dependently decreased adenyl cyclase activity in the absence of endogenous norepinephrine, suggesting inverse agonism, in  a hamster kidney cell line transfected with baculovirus encoding human beta-1 adrenergic receptors. A separate comparison of the magnitude of inverse agonism among different BB by this group showed that it was prominent in metoprolol, minimal in bucindolol, and moderate in carvedilol (inhibition of adenyl cyclase activity 60%, 38%, and 55%, respectively).

The clinical significance of inverse agonism in heart failure patients has not been shown. Gong and colleagues showed that the inverse agonist ICI 118,551 had minimal inverse agonism on the contraction of isolated non-failing cardiomyocytes, but had profound inverse agonism in failing myocytes, showing this pharmacologic profile is important in heart failure. Bristow and colleagues showed that propranolol and metoprolol with inverse agonism decreased cardiac output and increased pulmonary capillary wedge pressure. Carvedilol and bucindolol with modest inverse agonism coupled with vasodilatory activity were associated with minimal hemodynamic deterioration and decreased pulmonary capillary wedge pressure.

In the MERIT-HF trial, metoprolol decreased adverse cardiac effects during the titration period compared to placebo. However, in moderate heart failure, adverse cardiac events were increased with metoprolol during the titration period. In contrast, in more advanced heart failure, the COPERNICUS study showed no such trend. The withdrawal rate from the study was essentially the same between carvedilol and placebo. This different finding may be explained by the difference in inverse agonism between carvedilol and metoprolol.

Anti-adrenergic effect

The effect of the BB on the density of beta-adrenergic receptors is another critical pharmacologic property. This group showed that the number of receptors markedly increased with metoprolol, but decreased with carvedilol in chick heart cells expressing predominantly beta-1 adrenergic receptors. This suggests that carvedilol may exert a more potent anti-adrenergic effect than metoprolol.

Work by Gilbert and colleagues showed that metoprolol increased and carvedilol decreased the number of receptors in a biopsy sample from the right ventricle. Coronary sinus norepinephrine concentration was significantly decreased by carvedilol but not by metoprolol. In this regard, carvedilol exerts a more potent anti-adrenergic effect than metoprolol, because carvedilol does not elicit upregulation of beta-adrenergic receptors.

This group showed in patients with mild to moderate heart failure that the increase of delta double product during maximal exercise is normalized by an increase in plasma norepinephrine concentration, which is a parameter for adrenergic responsiveness (Figure 2). Carvedilol but not metoprolol significantly decreased this parameter during the study, suggesting that carvedilol exerts a more potent antiadrenergic effect than metoprolol during exercise.

The magnitude of increase in LVEF was larger with carvedilol than with metoprolol in the largest study to compare the two drugs. In contrast, maximal oxygen consumption during exercise was significantly increased with metoprolol but not by carvedilol. These results may reflect the difference in antiadrenergic effect during stress between the two drugs.

Idiopathic cardiomyopathy (IDCM) is a relatively common cause of heart failure in Japan. About 40% of such patients have autoantibodies directed against beta-1 adrenergic receptors. Immunoglobin G fraction isolated from rabbit serum immunized by the second extracellular loop of beta-1 adrenergic receptors, dose-dependently increased adenyl cyclase activity in rabbit cardiac membrane preparation, indicating that this autoantibody has an agonist-like effect. Bispoprolol inhibited adenyl cyclase activity in the absence of IgG or endogenous norepinephrine, suggesting inverse agonism in a study by this group. Bisoprolol completely abolished the agonist-like action of the autoantibodies.

To determine the clinical significance of the autoantibody directed against beta-1 adrenergic receptors, Yoshikawa and colleagues studied 104 patients with IDCM. The presence of the autoantibody was associated with high-risk ventricular tachycardia on Holter monitoring. There was no difference for heart failure death between patients with and without autoantibodies, but sudden cardiac death was significantly higher in patients with the autoantibody than those without (p=0.0219. Cox proportional hazards analysis revealed that the presence of the autoantibody was an independent predictor for sudden cardiac death and low EF. BB use was a negative predictor for high-risk ventricular tachycardia in patients with autoantibodies. This finding suggests that BB are useful to prevent sudden cardiac death (SCD) from serious ventricular arrhythmias in autoantibody-positive with IDCM.

In summary, significant differences in the pharmacologic profile of metoprolol and carvedilol exist. Inverse agonism, an agonist-independent receptor inactivation, is more prominent with metoprolol than carvedilol. This pharmacologic property may be relevant to adverse cardiac events during the introduction of beta blocker therapy in severe heart failure. Metoprolol, but not carvedilol, caused up-regulation of beta-adrenergic receptors. Carvedilol decreased the number of receptors in an in vitro experiment. In patients with mild to moderate heart failure, carvedilol exerts a more potent antiadrenergic effect during exercise than metoprolol. The presence of an autoantibody directed against beta-1 adrenergic receptors are associated with SCD, related to serious ventricular arrhythmias in patients with IDCM. The presence of inverse agonism seems to be an advantage in patients with mild heart failure from IDCM with autoantibodies directed against beta-adrenergic receptors.

The Role of Angiotensin Converting Enzyme Inhibitors (ACE-I), Angiotensin II Type I Receptor Antagonist (ARBs) and Aldosterone Receptor Blockers (AB) in Chronic Heart Failure (HF)

Bertram Pitt
University of Michigan School of Medicine, Ann Arbor, Michigan

The RALES study randomized patients with severe heart failure to Aldactone™ spironolactone and placebo, and showed a 30% reduction in all-cause mortality, from a reduction in sudden cardiac death (SCD) and progressive heart failure. This strategy in severe heart failure is being adopted in many parts of the world.

Spironolactone is known to cause gynecomastia and breast pain in men (about 10% of men in RALES) and menstrual irregularities in women. Although this may not be a major defect in patients with severe heart failure, this prohibits the application of this strategy in less severely ill patients, patients with mild to moderate heart failure, asymptomatic left ventricular dysfunction, and hypertension.

A new aldosterone blocking agent, eplerenone, is similar in its action to spironolactone, but it is more specific for the aldosterone receptor and does not bind to androgen and prostogen receptors and does not appear to cause gynecomastia, breast pain, and menstrual irregularities. This new compound may have wider applicability and hence intensive study has been underway.

In the EPHESUS study, eplerenone was studied in patients with AMI with systolic dysfunction (LVEF ≤ 40) and rales in non-diabetic patients. Patients were treated with standard therapy and randomized to eplerenone (n=3,100) starting at 25 mg daily for 1 month and uptitrated to 50 mg daily or to placebo (n=3,100). Patients were randomized between 3 and 14 days post-MI, the mean time was 7.3 days. The trial was carried out until it reached 1,012 deaths. The two primary endpoints were all-cause mortality and the combination of cardiovascular mortality and CV hospitalizations (MI, stroke, heart failure, ventricular arrhythmias). In contrast to the RALES study in which only 10.5% of patients were on beta blockade, 74% of EPHESUS patients were receiving beta blockers.

Mechanisms for efficacy of angiotensin blockade

The RALES trial showed that the diuretic effect of aldosterone blockade did not appear to be the major mechanism for reducing mortality. In RALES patients with class IV heart failure had a higher sodium retention score than patients in class III, but there was no difference between the patients randomized to spironolactone or placebo, suggesting that although there may have been some diuretic effect of spironolactone it did not appear to account for the major benefit.

Aldosterone plays a critical role in many other neurohumoral pathways. There are a number of vicious cycles. For example, aldosterone upregulates tissue ACE activity and thereby causes more angiotensin II which causes more aldosterone. Another cycle is with endothelin-1, affects on norepinephrine, and vasopressin. Many of these neurohormones combine, especially aldosterone, to increase NADH/NADPH oxidases in the vascular wall, cause the release of free radicals, and thereby stimulating various signaling pathways, such as NF-κB and AP-1 and destroy nitric oxide (NO).

In the lipid-fed rabbit model, a marked increase in vascular NADH/NADPH was seen compared to normal control rabbit with saline in work by Pitt and colleagues. Eplerenone nearly eliminated the NADH/NADPH activity. Free radical production was markedly increased in this model because of the stimulation of NADH/NADPH, but it was significantly and markedly decreased with eplerenone. Normal animals vasodilated whereas the lipid-fed model had endothelial dysfunction in response to acetylcholine; eplerenone caused significant improvement but not a total correction of endothelial function.

Work by Bauersachs and colleagues in the rat model compared the ACE inhibitor trandolapril to spironolactone and showed that spironolactone decreases NADH/NADPH and improves NO availability by decreasing free radical formation, whereas the ACE inhibitor trandolapril improved NO synthase. Combining the drugs caused a marked improvement in NO and completely corrected endothelial function in the animal models.

Farquharson and colleagues randomized patients with mild to moderate heart failure who had been on an ACE inhibitor for 3 months to spironolactone or placebo. Spironolactone caused a significant improvement in endothelial function in response to acetylcholine compared to placebo (170% change vs 99% change in FBF, respectively). This may be one important mechanism for aldosterone blockers because patients with heart failure have a high incidence of endothelial dysfunction and a high circulating level of free radicals.

Work by Ganten and Luft in the double transgenic mouse showed that aldosterone is an important stimulator of the NF-κB and AP-1 signaling pathway. Aldosterone and angiotensin II were compared in this model showing that angiotensin II is perhaps a better stimulator of NF-κB whereas aldosterone is a better stimulator of the AP-1 signaling pathway. Both angiotensin II and aldosterone activate both ways.

Work in an animal model has shown that aldosterone causes a marked increase in various adhesion molecules and cytokines. Cox-2, osteopontin, and MCP-1 are upregulated. There is marked microvascular inflammation, as a result of aldosterone stimulation, causing subsequent fibrosis. Angiotensin blockade can block all of these effects. A model of aldosterone/salt hypertensive rats showed marked fibrosis, which was significantly prevented with eplerenone. This was also seen in a substudy of the RALES trial, patients randomized to spironolactone had a marked decrease in ongoing collagen formation, which seemed to correlate with the improvement in survival. Suzuki and co-workers showed in an animal model that eplerenone decreases levels of MMP 2 and MMP 9 and thereby prevents progressive left ventricular remodeling.

Aldosterone improved heart rate variability, which may be a mechanism by which it prevents sudden cardiac death. So, it restores autonomic balance by improving vagal tone through an increased availability of NO. Many studies have shown that increased heart rate variability correlates with a reduction in SCD.

Aldosterone prevents the uptake of norepinephrine into the myocardium and increases circulating catecholamine levels. Conversely, aldosterone blockade improved myocardial norepinephrine uptake and decreases circulating catecholamine levels.

Cytokines and TNF-alpha are increased after myocardial damage. TNF-alpha increases prostaglandin-E2, which can cross the blood-brain barrier and stimulate central mineralocorticoid receptors. Their activation causes a central increase in sympathetic drive, salt appetite, blood volume, hypertension, AVP, angiotensin II binding to the AT-1 receptor, and a further increase in TNF-alpha. This is another vicious cycle, and the activation of the central sympathetic drive may be an important mechanism in SCD which can be turned off by aldosterone-receptor blocking agents which can cross the blood-brain barrier.

Another new concept is that aldosterone blocking agents may be affected when serum levels of aldosterone are not elevated. One explanation may be that the mineralocorticoid receptor can be occupied, but it can be occupied also by cortisol. Normally cortisol is rapidly degraded by the enzyme 11-ßHSBD2, and the cortisone cannot occupy the receptor. So, normally all the aldosterone occupies the receptor, however, during oxidative stress that enzyme is down-regulated and there may be more cortisol available and it may occupy the mineralocorticoid receptor. An agent such as spironolactone or eplerenone can block that receptor regardless of whether or not it is occupied and activated by aldosterone or cortisol. This may in part explain why in many of our studies even where serum aldosterone levels are not elevated there is a striking effect of aldosterone blockade.

The current concepts of aldosterone blockade are: The mineralocorticoid receptor can be stimulated by aldosterone or cortisol, and this receptor can be blocked and the effects of either aldosterone or cortisol on this receptor. This receptor has a number of effects: the classic effects on the kidney; increases vascular NADH/NADPH, leading to an increase in free radicals; reduction in NO which has many important adverse effects; increase of free radicals; stimulation of NF-κB and AP-1, adhesion molecules, vascular inflammation, fibrosis and hypertrophy. All of these may lead to hypertension, heart failure, and ischemic events. The mineralocorticoid receptor may centrally and peripherally effect autonomic balance and cause changes in heart rate variability, baroreceptor function and norepinephrine uptake, which can lead to sudden death. Blocking this receptor has a number of beneficial effects, and may in part explain the results of the RALES and EPHESUS trials.

Disease Management for Chronic Heart Failure: Opportunity and Application

Harlan M. Krumholz
Yale University School of Medicine, New Haven, CT

The need for a disease management strategy in heart failure is illustrated by a typical heart failure patient. She is a 76-year-old grandmother with diabetes, hypertension, arthritis, and mild chronic obstructive pulmonary disease, and heart failure. The medications for the different co-morbidities can work at cross-purposes, perhaps helping one condition but perhaps adding risk to another condition. Polypharmacy also affects compliance and affordability of treatment, among other factors.

Concerns at hospital discharge include 1) inadequate explanation and understanding of the medications, and 2) lack of optimal communication between the hospital and the follow-up physicians, adding to patient confusion about treatment regimen, which can lead to hospital re-admission. A vicious cycle is often set up. Despite the advances in the treatment of heart failure, the medical system is failing these patients. The patients are repeatedly hospitalized and their quality of life (QOL) is compromised. More global thinking about the cluster of conditions of the patient and how to help the patient manage them is required.

The conditions commonly present in patients with heart failure are hypertension 60%, renal sufficiency 50%, and diabetes 33%, according to a national survey in the US. Further, the outcomes are 10% mortality rate at 30-days, 25% at 6 months, and 35% at 1 year. The rate of hospitalization is 1 in 5 patients at 30 days, 1 in 2 patients at 6 months, and 66% at 1 year.

The burden on health care system is illustrated by a survey in the state of Connecticut conducted by Krumholz and colleagues. The all-cause hospital re-admission for a patient with heart failure was $7000. A low-risk or high-risk group for readmission could not be identified.

Importantly, the patient composition in clinical practice and clinical trials differ. In clinical practice, 50% of patients are women with an average age of 75 years, while only 20% of the trial population is women and the average age is 60 years, according to a systematic review of clinical heart failure trials by Krumholz and colleagues.

Underutilization of appropriate testing and treatments is known. A national survey showed that assessment of left ventricular ejection fraction (LVEF) while hospitalized or documented from a prior measurement occurred in only 60% of patients. ACE inhibitors for LV systolic dysfunction were prescribed for only 60% of patients. In some patients a therapeutic substitution of an angiotensin receptor blocker for an ACE inhibitor was made, although this is not supported by the guideline.

Communications gaps in patient care are affecting outcomes. This is seen in the limited counseling at discharge about medications, weight monitoring, diet, activity, follow-up appointments, and management of symptoms, as shown in the national survey. Systems must be developed to ensure discharge communication occurs.

Gaps in treatment, education, and continuity of care exist, as shown by the national survey and other data. The health care system is designed to react to illness, not to be proactive and prepared to prevent these exacerbations.

Disease management for heart failure

Patient management includes 1) ensuring the patients has the best treatment, and 2) has the information, skills and support to make good decisions to manage their heart failure in partnership with their physician and other caregivers.

Disease management provides support to patients and health care providers. It ensures that patients receive needed treatment and information. It combines a prepared patient and family with a prepared health care system that seeks to be proactive and prevent disease.

Krumholz and colleagues studied the effect of an educational strategy on outcomes. The educational strategy was designed to provide the patient with information about their illness, the relation between their medication regimen and their health, the relation between their health behaviors and their health, about early signs of decompensation, and where and when to obtain assistance. The education strategy included in-hospital counseling and phone calls at intervals to reinforce the concepts. In the educational strategy group, survival free of heart failure readmission was 30%, all-cause readmission or death 37%, cardiovascular readmission or death 40%, and heart failure readmission 43%. The hospital costs were higher in the control group by an average $7000; $25,000 vs $14,000 per year. The educational strategy was cost saving.

A systematic review of 17 studies of post-discharge support showed a remarkable 26% risk of readmission in heart failure patients. The interventions included single-home visits, increased clinic follow-up and telephone contact.

The generalizability of these findings to other populations is needed. Payment remains a problem. Despite the remarkable results, no one is willing to pay for the preventive intervention. Systems continue to focus on paying for acute illness, not prevention. The value of these approaches has not been integrated into the health care system. To put this in perspective, a drug that reduced readmission by 25% thus saving money and had no side effects would find its way into the health care system.